Morpholinone and morpholine derivatives and uses thereof

ABSTRACT

This invention is directed to morpholinone and morpholine derivatives which are selective antagonists for human α 1a  receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia, sympathetic mediated pain, migraine, and for the treatment of any disease where the antagonism of the α 1a  receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Throughout this application, various references are referred to withinparentheses. Disclosures of these publications in their entireties arehereby incorporated by reference into this application to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

The designation “α_(1a) ” is the appellation recently approved to theIUPHAR Nomenclature Committee for the previously designated “α_(1c)”cloned subtype as outlined in the Pharmacological Reviews (Hieble, etal. (1995) Pharmacological Reviews 47: 267 270). The designation α_(1a)is used throughout this application and the supporting tables andfigures to refer to this receptor subtype. At the same time, thereceptor formerly designated α_(1a) was renamed α_(1d). The newnomenclature is used throughout this application. Stable cell linesexpressing these receptors are described herein; however, these celllines were deposited with the American Type Culture Collection (ATCC)under the old nomenclature (infra).

Benign Prostatic Hyperplasia (BPH), also called Benign ProstaticHypertrophy, is a progressive condition which is characterized by anodular enlargement of prostatic tissue resulting in obstruction of theurethra. This results in increased frequency of urination, nocturia, apoor urine stream, and hesitancy or delay in starting the urine flow.Chronic consequences of BPH can include hypertrophy of bladder smoothmuscle, a decompensated bladder, and an increased incidence of urinarytract infection. The specific biochemical, histological, andpharmacological properties of the prostate adenoma leading to thebladder outlet obstruction are not yet known. However, the developmentof BPH is considered to be an inescapable phenomenon for the aging malepopulation. BPH is observed in approximately 70% of males over the ageof 70. Currently, in the United States, the method of choice fortreating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17: 651,1990). Over 400,000 prostatectomies are performed annually (data from1986). The limitations of surgery for treating BPH include the morbidityrate of an operative procedure in elderly men, persistence or recurrenceof obstructive and irritative symptoms, as well as the significant costof surgery. A medicinal alternative to surgery is clearly verydesirable.

α-Adrenergic receptors (McGrath et al., Med. Res. Rev. 2, 407-533, 1989)are specific neuroreceptor proteins located in the peripheral andcentral nervous systems on tissues and organs throughout the body. Thesereceptors are important switches for controlling many physiologicalfunctions and, thus, represent important targets for drug development.In fact, many α-adrenergic drugs have been developed over the past 40years. Examples include clonidine, phenoxybenzamine and prazosin (fortreatment of hypertension), naphazoline (a nasal decongestant), andapraclonidine (for treatment of glaucoma). α-adrenergic drugs can bebroken down into two distinct classes: agonists (e.g., clonidine andnaphazoline), which mimic the receptor activation properties of theendogenous neurotransmitter norepinephrine, and antagonists (e.g.,pheoxybenzamine and prazosin), which act to block the effects ofnorepinephrine. Many of these drugs are effective, but also produceunwanted side effects (e.g., clonidine produces dry mouth and sedationin addition to its antihypertensive effects).

During the past 15 years, a more precise understanding of α-adrenergicreceptors and their drugs has evolved through increased scientificscrutiny. Prior to 1977, only one α-adrenergic receptor was kown toexist. Between 1977 and 1988, it was accepted by the scientificcommunity that at least two α-adrenergic receptors, α₁ and α₃, existedin the central and peripheral nervous systems. Since 1988, newtechniques in molecular biology have led to the identification of atleast six α-adrenergic receptors which exist throughout the central andperipheral nervous systems: α_(1a) (new nomenclature), α_(1b), α_(1d)(new nomenclature), α_(2a), α_(2b) and α_(2c) (Bylund, D. B., FASEB J 6:832, 1992). In many cases, it is not known precisely which physiologicalresponses in the body are controlled by each of these receptors. Inaddition, current α-adrenergic drugs are not selective for anyparticular α-adrenergic receptor. Many of these drugs produce untowardside effects that may be attributed to their poor α-adrenergic receptorselectivity.

Since the mid 1970's, nonselective α antagonists have been prescribed totreat BPH. In 1976, M. Caine et al. (Brit. J. Urol. 48: 955, 1976)reported that the nonselective α-antagonist phenoxybenzamine was usefulin relieving the symptoms of BPH. This drug may produce its effects byinteracting with α-receptors located on the prostate. However, this drugalso produces significant side effects such as dizziness and aethenia,which severely limit its use in treating patients on a chronic basis.More recently, the α-adrenergic antagonists prazosin and torazosin havealso been found to be useful for treating BPH. However, these drugs alsoproduce untoward side effects. It has recently been discovered that theα_(1a) receptor is responsible for mediating the contraction of humanprostate smooth muscle (Gluchowski, C. et al., WO 94/10989, 1994;Forray, C. et al., Mol. Pharmacol. 45: 703, 1994). This discoveryindicates that the α_(1a) antagonists may be effective agents for thetreatment of BPH with decreased side effects. Further studies haveindicated that the α_(1a) receptor may also be present in other lowerurinary tract tissues, such as urethral smooth muscle (Ford et al., Br.J. Pharmacol. 114; 24P, 1995).

SUMMARY OF THE INVENTION

This invention is directed to a compound having the structure:

where W is O, S, or NR₈; wherein R₈ is independently H, straight chainedor branched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

where Y is independently O or S;

where R₂ is aryl or heteroaryl; wherein the aryl or heteroaryl may besubstituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; and wherein n independently is an integer from 0to 7 inclusive;

where R₃ is independently H; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl;

where R₄ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl,or phenyl or benzyl; wherein the phenyl or benzyl may be substitutedwith one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y) R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl; and wherein t independently is an integer from 1 to 4inclusive;

where R₅ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl;wherein the phenyl or benzyl may be substituted with one or more of F;Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

where R₆ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl,or phenyl or benzyl; wherein the phenyl or benzyl may be substitutedwith one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

where R₇ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl;wherein the phenyl or benzyl may be substituted with one or more of F;Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

where q is an integer from 0 to 4 inclusive;

where each R₈, n, and t independently is as defined above;

where R₁ is

wherein each R₉ is H; straight chained or branched C₁-C₇ alkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C₅-C₇cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl maybe substituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;

wherein each R₁₀ is H; F; —OH; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; (CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; aryl orheteroaryl; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl,aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; orC₅-C₇ cycloalkenyl; wherein the alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl may be substituted with one or more aryl or heteroaryl;wherein the aryl or heteroaryl may be substituted with one or more of F;Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl; straightchained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, or polyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;

wherein each R₁₁ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

wherein each R₁₂ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl;

wherein R₁₃ is H, C₁-C₇ alkyl, —C(O)R₂, aryl, heteroaryl, C₁-C₇ alkylsubstituted with one or two aryl, or C₁-C₇ alkyl substituted with one ortwo heteroaryl; wherein the aryl or heteroaryl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇aminoalkyl, alkenyl, or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

wherein R₁₄ is H, straight chained or branched C₁-C₇ akyl;

wherein Z is O, S, NR₁₄, CO, CH₂,

wherein Y₁, Y₂, and Y₃ independently are H; F; Cl; Br; I; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl;

wherein each m is independently 1 or 2;

wherein each p is independently an integer from 0 to 2 inclusive;

wherein J is

or C₂-C₇ alkenyl;

wherein each R₁₅ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

wherein each R₁ is independently H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

wherein each R₁₇ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; —C(Y)R₈; —C(Y)N(R₈)₂; —CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

wherein each R₁₈ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

wherein L is S, O, or N(R₈);

wherein u is an integer from 0 to 1 inclusive;

or a pharmaceutically acceptable salt thereof.

This invention provides for a pharmaceutical composition comprising atherapeutically effective amount of any one of the compounds describedherein and a pharmaceutically acceptable carrier.

This invention provides for a method of treating a subject sufferingfrom benign prostatic hyperplasia which comprises administering to thesubject an amount of any one of the compounds described herein effectiveto treat benign prostatic hyperplasia.

This invention provides for a method of treating a subject sufferingfrom high intraocular pressure which comprises administering to thesubject an amount of any one of the compounds described herein effectiveto lower intraocular pressure.

This invention provides for a method of treating a subject sufferingfrom a disorder associated with high cholesterol which comprisesadministering to the subject an amount of any one of the compoundsdescribed herein effective to inhibit cholesterol synthesis.

This invention provides for a method of treating a subject sufferingfrom cardiac arrhythmia which comprises administering to the subject anamount of any one of the compounds described herein effective to treatcardiac arrhythmia.

This invention provides for a method of treating a subject sufferingfrom impotency which comprises administering to the subject an amount ofany one of the compounds described herein effective to treat impotency.

This invention provides for a method of treating a subject sufferingfrom sympathetically mediated pain which comprises administering to thesubject an amount of any one of the compounds described herein effectiveto treat sympathetically mediated pain.

This invention provides for a method of treating a subject sufferingfrom migraine which comprises administering to the subject an amount ofany one of the compounds described herein effective to treat migraine.

This invention provides for a method of treating a disease which issusceptible to treatment by antagonism of the α_(1a) receptor whichcomprises administering to the subject an amount of any one of thecompounds described herein effective to treat the disease.

This invention provides for a method of treating a subject sufferingfrom benign prostatic hyperplasia which comprises administering to thesubject an amount of any one of the compounds described herein incombination with a 5-alpha reductase inhibitor effective to treat benignprostatic hyperplasia.

This invention provides for a pharmaceutical composition comprising atherapeutically effective amount of any one of the compounds describedherein in combination with a therapeutically effective amount offinasteride and a pharmaceutically acceptable carrier.

This invention provides for a method of relaxing lower urinary tracttissue which comprises contacting the lower urinary tract tissue with anamount of any one of the compounds described herein effective to relaxlower urinary tract tissue.

This invention provides for a method of relaxing lower urinary tracttissue in a subject which comprises administering to the subject anamount of any one of the compounds described herein effective to relaxlower urinary tract tissue.

This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein and a pharmaceutically acceptable carrier.

This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein with a therapeutically effective amount of finasterideand a pharmaceutically acceptable carrier.

This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein and a pharmaceuticallyacceptable carrier.

This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein with a therapeuticallyeffective amount of finasteride and a pharmaceutically acceptablecarrier.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1F

FIGS. 1A-1F show the structures of the compounds described herein in theExamples.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides for a compound having the structure:

where W is O, S, or NR₈; wherein R₈ is independently H, straight chainedor branched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

where Y is independently O or S;

where R₂ is aryl or heteroaryl; wherein the aryl or heteroaryl may besubstituted with one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂;—SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl; and wherein n independently is an integer from 0to 7 inclusive;

where R₃ is independently H; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl;

where R₄ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈ straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl,or phenyl or benzyl; wherein the phenyl or benzyl may be substitutedwith one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl; and wherein t independently is an integer from 1 to 4inclusive;

where R₅ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y) R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl;wherein the phenyl or benzyl may be substituted with one or more of F;Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

where R₆ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl,or phenyl or benzyl; wherein the phenyl or benzyl may be substitutedwith one or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

where R₇ is H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained orbranched C₁-C₇ alkyl, straight chained or branched C₂-C₇ alkenyl oralkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl;wherein the phenyl or benzyl may be substituted with one or more of F;Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

where q is an integer from 0 to 4 inclusive;

where each R₈, n, and t independently is as defined above;

where R₁ is

wherein each R₉ is H; straight chained or branched C₁-C₇ alkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C₅-C₇cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl maybe substituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;

wherein each R₁₀ is H; F; —OH; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; (CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; aryl orheteroaryl; straight chained or branched C₁-C₇ alkyl, hydroxyalkyl,aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; orC₅-C₇ cycloalkenyl; wherein the alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl orcycloalkenyl may be substituted with one or more aryl or heteroaryl;wherein the aryl or heteroaryl may be substituted with one or more of F;Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl; straightchained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl, or polyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;

wherein each R₁₁ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —C₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

wherein each R₁₂ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl or C₅-C₇ cycloalkenyl;

Q wherein R₁₃ is H, C₁-C₇ alkyl, —C(O)R₂, aryl, heteroaryl, C₁-C₇ alkylsubstituted with one or two aryl, or C₁-C₇ alkyl substituted with one ortwo heteroaryl; wherein the aryl or heteroaryl may be substituted withone or more of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇aminoalkyl, alkenyl, or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl;

wherein R₁₄ is H, straight chained or branched C₁-C₇ akyl;

wherein Z is O, S, NR₁₄, CO, CH₂,

wherein Y₁, Y₂, and Y₃ independently are H; F; Cl; Br; I; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl;or C₅-C₇ cycloalkenyl;

wherein each m is independently 1 or 2;

wherein each p is independently an integer from 0 to 2 inclusive;

wherein J is

or C₂-C₇ alkenyl;

wherein each R₁₅ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;

wherein each R₁₆ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl, or C₅-C₇ cycloalkenyl;

wherein each R₁₇ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; —C(Y)R₈; —C(Y)N(R₈)₂; —CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

wherein each R₁₈ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; straight chained or branched C₁-C₇alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl;

wherein L is S, O, or N(R₈);

wherein u is an integer from 0 to 1 inclusive;

or a pharmaceutically acceptable salt thereof.

The invention also provides for the (−) and (+) enantiomers of allcompounds of the subject application described herein.

The invention further provides for the cis and trans enantiomers of allof the compounds of the subject application described herein. It isnoted herein that the terms “cis” and “trans” correspond to relativestereochemistry, as determined, for example, by NOE (Nuclear OverhauserEffect) experiments.

The compounds of the present invention are preferably at least 80% pure,more preferably at least 90% pure, and most preferably at least 95%pure.

In the present invention, the term “aryl” is used to include phenyl,benzyl, benzoyl, or naphthyl; and the term “heteroaryl” is used toinclude pyrazinyl, pyrrolyl, furanyl, thiophenyl, pyridyl, imidazolyl,indolyl, aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl,benzfuranyl, or quinolyl.

The compounds of this invention exhibit greater affinity, preferably atleast ten-fold greater affinity, for the human α_(1a) receptor over thehuman α_(1b) or human α_(1d) receptors.

In one embodiment, W is O.

In another embodiment, J is

In another embodiment, R₁ is

In another embodiment, R₉ is aryl or heteroaryl, wherein the aryl orheteroaryl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; and R₁₀ is H; —CN; —OH; —CO₂R₉;aryl or heteroaryl; wherein the aryl or heteroaryl may be substitutedwith one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; —SO₂R₈;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, orpolyfluoroalkyl.

In another embodiment of the invention, the compound has the structure:

wherein R₂ is phenyl; wherein the phenyl may be substituted with one ormore of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl.

In another embodiment, J is

In another embodiment, R₁ is

In another embodiment, R₉ is phenyl or pyridyl, wherein the phenyl orpyridyl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl;

R₁₀ is H, —CN, —OH, —CO₂R₈, or phenyl; wherein the phenyl may besubstituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈, —CN; —NO₂;—N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; and

R₁₃ is phenyl; wherein the phenyl may be substituted with one or more ofF; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ aminoalkyl,alkenyl, or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl.

In another preferred embodiment, the R₄ is H, alkyl, cycloalkyl, —CO₂R₃,or —C(Y)N(R₃)₂; and R₁₀ is H, F, C₁-C₇ alkyl, C₁-C₇ alkoxy, or OH.

The invention provides for a pharmaceutical composition comprising atherapeutically effective amount of any of the compounds described aboveand a pharmaceutically acceptable carrier. In the subject invention, a“therapeutically effective amount” is any amount of a compound which,when administered to a subject suffering from a disease against whichthe compounds are effective, causes reduction, remission, or regressionof the disease.

In one embodiment, the therapeutically effective amount is an amountfrom about 0.01 mg per subject per day to about 800 mg per subject perday, preferably from about 0.01 mg per subject per day to about 500 mgper subject per day, more preferably from about 0.01 mg per subject perday to about 250 mg per subject per day, more preferably from about 0.1mg per subject per day to about 60 mg per subject per day and mostpreferably from about 1 mg per subject per day to about 20 mg persubject per day. In the practice of this invention, the“pharmaceutically acceptable carrier” is any physiological carrier knownto those of ordinary skill in the art useful in formulatingpharmaceutical compositions.

In one embodiment the pharmaceutical carrier may be a liquid and thepharmaceutical composition would be in the form of a solution. Inanother embodiment, the pharmaceutically acceptable carrier is a solidand the composition is in the form of a powder or tablet. In a furtherembodiment, the pharmaceutical carrier is a gel and the composition isin the form of a suppository or cream. In a further embodiment thecompound may be formulated as a part of a pharmaceutically acceptabletransdermal patch.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular, intrathecal,epidural, intraperitoneal or subcutaneous injection. Sterile solutionscan also be administered intravenously. The compounds may be prepared asa sterile solid composition which may be dissolved or suspended at thetime of administration using sterile water, saline, or other appropriatesterile injectable medium. Carriers are intended to include necessaryand inert binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

In another embodiment, any one of the compounds described hereinadditionally does not cause a fall in blood pressure at dosageseffective to alleviate benign prostatic hyperplasia.

The invention provides a method of treating a subject suffering frombenign prostatic hyperplasia, which comprises administering to thesubject any one of the compounds described herein effective to treatbenign prostatic hyperplasia. In a preferred embodiment, the compound ofthe pharmaceutical composition additionally does not cause a fall inblood pressure at dosages effective to alleviate benign prostatichyperplasia. In a preferred embodiment, the compound effects treatmentof benign prostatic hyperplasia by relaxing lower urinary tract tissueand in particular where lower urinary tract tissue is prostatic smoothmuscle.

In the practice of this invention, the term “lower urinary tract tissue”is used to include prostatic capsule, prostate urethra, urethral smoothmuscle, prostatic smooth muscle, and bladderneck.

The invention further provides a method of treating a subject sufferingfrom elevated intraocular pressure, which comprises administering to thesubject one of the compounds described herein effective to lowerintraocular pressure.

The invention further provides a method of treating a subject sufferingfrom a disorder associated with elevated blood cholesterol, whichcomprises administering to the subject one of the compounds describedherein effective to inhibit cholesterol synthesis.

The invention provides a method of treating a subject suffering fromcardiac arrhythmia, which comprises administering to the subject one ofthe compounds described herein effective to treat cardiac arrhythmia.

The invention further provides a method of treating a subject sufferingfrom impotency, which comprises administering to the subject one of thecompounds described herein effective to treat impotency.

The invention further provides a method of treating a subject sufferingfrom sympathetically mediated pain, which comprises administering to thesubject one of the compounds described herein effective to treatsympathetically mediated pain.

This invention provides a method of treating a subject suffering frommigraine which comprises administering to the subject one of thecompounds described herein effective to treat migraine.

The invention also provides a method of treating a disease which issusceptible to treatment by antagonism of the α_(1a) receptor, whichcomprises administering to the subject one of the compounds describedherein effective to treat the disease.

The invention provides a method of treating a subject suffering frombenign prostatic hyperplasia, which comprises administering to thesubject one of the compounds described herein in combination with a5-alpha reductase inhibitor effective to treat benign prostatichyperplasia. In one preferred embodiment the 5-alpha reductase inhibitoris finasteride.

This invention provides for a pharmaceutical composition comprising atherapeutically effective amount of any one of the compound describedherein in combination with a therapeutically effective amount offinasteride and a pharmaceutically acceptable carrier. This inventionalso provides for a pharmaceutical composition comprising any one of thecompounds described herein present in an amount from about 0.01 mg toabout 800 mg and the therapeutically effective amount of the finasterideis about 5 mg. In one embodiment, the pharmaceutical composition is anyone of the compounds described herein present in an amount from about0.1 mg to about 60 mg and the therapeutically effective amount offinasteride is about 5 mg. In another embodiment, the pharmaceuticalcomposition is any one of the compounds described herein present in anamount from about 1 mg to about 20 mg and the therapeutically effectiveamount of finasteride is about 5 mg.

The invention further provides a method of relaxing lower urinary tracttissue which comprises contacting the lower urinary tract tissue with anamount of one of the compounds described herein effective to relax lowerurinary tract tissue. In one embodiment the lower urinary tract tissueis prostatic smooth muscle. In one preferred embodiment, the compoundadditionally does not cause a fall in blood pressure when it iseffective to relax lower urinary tract tissue.

The invention provides a method of relaxing lower urinary tract tissuein a subject which comprises administering to the subject an amount ofone of the compounds described herein effective to relax lower urinarytract tissue. In one embodiment the lower urinary tract tissue isprostatic smooth muscle. In one preferred embodiment, the compoundadditionally does not cause a fall in blood pressure when it iseffective to relax lower urinary tract tissue.

This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein and a pharmaceutically acceptable carrier.

This invention provides for a pharmaceutical composition made bycombining a therapeutically effective amount of any one of the compoundsdescribed herein with a therapeutically effective amount of finasterideand a pharmaceutically acceptable carrier.

This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein and a pharmaceuticallyacceptable carrier.

This invention provides for a process for making a pharmaceuticalcomposition comprising combining a therapeutically effective amount ofany one of the compounds described herein with a therapeuticallyeffective amount of finasteride and a pharmaceutically acceptablecarrier.

Included in this invention are pharmaceutically acceptable salts andcomplexes of all of the compounds described herein. The salts includebut are not limited to the following acids and bases: inorganic acidswhich include hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, and boric acid; organic acids which include acetic acid,oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid,maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolicacid, lactic acid, and mandelic acid; inorganic bases which includeammonia; and organic bases which include methylamine, ethylamine,hydroxyethylamine, propylamine, dimethylamine, diethylamine,trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine,morpholine, piperazine, and guanidine. This invention further providesfor the hydrates and polymorphs of all of the compounds describedherein.

The present invention includes within its scope prodrugs of thecompounds of this inventions. In general, such prodrugs will befunctional derivatives of the compounds of the invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in Design of Prodrugs, ed. H. Bundgaard,Elsevier, 1985.

The present invention further includes metabolites of the compounds ofthe present invention. Metabolites include active species produced uponintroduction of compounds of this invention into the biological milieu.

One skilled in the art will readily appreciate that appropriatebiological assays will be used to determine the therapeutic potential ofthe claimed compounds for the treating the above noted disorders.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS I. Synthesis of Morpholinone Examples (Schemes 1and 2) 1. Synthesis of3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenylester (Scheme 1)

a. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone

To a solution of KOH (56 g, 1.0 mol) in MeOH (500 mL) was added3,4-difluoroacetophenone (15.6 g, 0.1 mol) dropwise over 15 min at 0° C.Phenyliodosodiacetate (64.4 g, 0.2 mol) was added in small portions overa 20 min period, and the resulting yellow-orange solution was stirredovernight at room temperature. The solvent was removed in vacuo toobtain a yellow-orange gum. The residue was dissolved in 100 mL of waterand 100 mL of brine and was thoroughly extracted with ethyl acetate(3×150 mL). The organic layer was dried over Na₂SO₄ and was decanted.The solvent was removed in vacuo to obtain 31.0 g of the acetal as thickyellow oil. It was dissolved in 200 mL of acetone and about 10 drops ofconcentrated sulfuric acid. The reaction mixture was stirred at roomtemperature for 2 hours until TLC analysis showed complete consumptionof the starting material. The solvent was removed in vacuo and the solidthat was obtained was first basified by adding saturated NaHCO₃ solutionand then it was extracted with ethyl acetate (300 mL). The organic layerwas separated and washed with brine. The organic layer was dried overMgSO₄, filtered, and the solvent was removed in vacuo to obtain a yellowsolid. The yellow solid was washed with cold hexane (to removeiodobenzene impurities) and dried to obtain 11.4 g (66% yield) of1-hydroxy-(3,4-difluorophenyl)-acetophenone as pale yellow solid. Theproduct was shown to be >90% pure by NMR and was used in the next stepwithout further purification.

b. 1-Hydroxy-(3,4-difluorophenyl)-acetophenone oxime

To a solution of l-hydroxy-(3,4-difluorophenyl)-acetophenone (6.0 g,34.9 mmol) in 150 mL of MeOH was added hydroxylamine hydrochloride (3.16g, 45.6 mmol) and sodium acetate (9.6 g, 69.6 mmol) at room temperatureand the resulting solution was stirred overnight. The solvent wasremoved and the residue was dissolved in methylene chloride (150 mL) andwas washed with 100 mL of saturated NaHCO₃ solution followed by brine.The organic layer was separated and dried over MgSO₄, filtered, and thesolvent was removed in vacuo to obtain1-hydroxy-(3,4-difluorophenyl)-acetophenone-oxime as a yellow solid (5.6g, 86%). It was used in the next step without any purification.

c. 2-Amino-2-(3,4-difluorophenyl)-ethanol

To a well stirred suspension of LiAlH₄ (3.4 g, 89.5 mmol) in THF (120mL) in a 3-necked round bottom flask fitted with a condenser and adropping funnel was added a solution of1-hydroxy-(3,4-difluorophenyl)-acetophenone-oxime (4.6 g, 24.6 mmol) inTHF (50 mL) dropwise at 0° C. The resulting greyish yellow suspensionwas heated to reflux for 2 hours. The reaction mixture was cooled to 0°C. and then carefully quenched sequentially with 3.4 mL of water, 3.4 mLof 3N NaOH, and 10 mL of water. The resulting suspension was filteredthrough a fritted glass funnel. To the residue was added 100 mL Et₂O andthe suspension was heated to reflux for 20 min. The suspension wasfiltered and was combined with the previous filtrate, dried over MgSO₄,filtered, and the solvent was removed in vacuo.2-Amino-2-(3,4-difluorophenyl)-ethanol was obtained as a yellow glassysyrup (4.1 g, 96%) which was used in the next step without furtherpurification.

Method A for the synthesis of 5-(3,4-difluoro-phenyl)morpholin-3-one:

d. 2-Chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide

To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol 2.6 g, 15.0mmol) in CH₂Cl₂ (15 mL) and 20% (by wt.) NaOH (15 mL) was added asolution of chloroacetyl chloride (1.32 mL, 16.5 mmol) in 15 mL ofCH₂Cl₂ at −10° C. dropwise under argon atmosphere. After the additionwas complete, the reaction mixture was stirred for 15 min and then itwas transferred to a separatory funnel. The organic layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (2×20 mL). The combinedorganic extracts were washed with a solution containing 10 mL of brineand 5 drops of concentrated HCl. The organic layer was dried over MgSO₄,filtered and the solvent was removed in vacuo to give a white solid. Itwas further purified with flash column chromatography on silica gel with1:1 hexane/EtOAc followed by EtOAc as the eluting system.2-Chloro-N-[1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-acetamide wasobtained as a white solid (2.6 g, 69.5% yield).

e. 5-(3,4-Difluoro-phenyl)-morpholin-3-one

To a suspension of sodium hydride (0.29 g, 11.39 mmol) in 48 mL THF wasadded a solution of2-chloro-N-[1-(3,4-difluoro-phenyl)-2-hydroxy-ethyl]-acetamide (2.6 g,10.4 mmol) in 48 mL THF dropwise via a dropping funnel at −25° C. over20 min. After the addition was over, the cooling bath was removed andthe reaction mixture was stirred at room temperature for 8 hours. TLCanalysis indicated a complete disappearance of the starting material.The reaction was quenched by adding a few crystals of ice. It wasextracted thoroughly with EtOAc (3×30 mL) and was washed with brine. Theorganic layer was separated and dried over MgSO₄. The organic layer wasfiltered and the solvent was removed in vacuo. The residue was suspendedin EtOAc and the white solid was collected via filtration which wasfound to be 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.8 g, 38% yield).

Method B for the synthesis of 5-(3,4-difluoro-phenyl)-morpholin-3-one:

f. 5-(3,4-difluoro-phenyl)-morpholin-3-one

To a suspension of NaH (8.0 mmol, 0.19 g) in 10 mL THF at 0° C. wasadded a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (7.51 mmol,1.3 g) in 20 mL THF dropwise via an addition funnel and after 30 minethyl chloroacetate was added dropwise via syringe. The orange coloredreaction mixture was stirred for 2 hours at 0° C. and then for 2 hoursat 35° C. The solvent was removed and the5-(3,4-difluoro-phenyl)-morpholin-3-one was isolated as a thick yellowoil (0.5 g). ¹H NMR showed that the product was about 85% pure and anyattempts to purify it further by column chromatography were notsuccessful. It was used in the next reaction as described below withoutfurther purification.

g. 3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester

To a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (0.34 g, 1.57mmol) in 10 mL of THF was added NaH (0.05 g, 1.9 mmol) and the resultingsolution was stirred for 30 min. It was then transferred via a syringeinto a solution of 4-nitrophenyl chloroformate in 20 mL of anhydrous THFat −78° C. under argon. The resulting solution was stirred for 2 hoursafter which the solvent was removed and the residue was purified bycolumn chromatography on silica gel with 1:1 hexane/CH₂Cl₂ followed byCH₂Cl₂ to obtain 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester as a colorless thick oil (0.31 g, 51%).

2. Synthesis of (+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (Scheme 2)

a. [1-(3,4-Difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butylester

To a solution of 2-amino-2-(3,4-difluorophenyl)-ethanol (8.6 g, 49.7mmol) in CHCl₃ (150 mL) at 0° C. was added a solution of di-tert-butyldicarbonate (11.4 g, 52.0 mmol) in CHCl₃ (50 mL) in one portion and theresulting solution was stirred overnight at room temperature. Thesolvent was removed in vacuo and the residue was subjected to columnchromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) toobtain [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butylester as white solid (10.0 g, 74%).

b. (+)-4-(3,4-Difluorophenyl)-oxazolidin-2-one

To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) atroom temperature was added a solution of[1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester(5.0 g, 18.3 mmol) in 20 mL THF via a dropping funnel at roomtemperature. The resulting suspension was stirred for 3 hours and thenquenched carefully with 10 mL of water. The biphasic mixture wasextracted with 100 mL of Et₂O, washed with brine, filtered, and thesolvent was removed in vacuo. The gummy residue thus obtained waspurified by column chromatography over silica gel (R_(f)=0.15, 3:2hexane-EtOAc) to obtain 4-(3,4-difluorophenyl)-oxazolidin-2-one as awhite flaky solid (2.8 g, 77%). M.P. 81-83° C.; ¹H NMR δ 4.13 (dd, J=6.6Hz, J=8.7 Hz, 1 H), 4.73 (t, J=8.7 Hz, 1 H), 4.94 (dd, J=6.6 Hz, J=8.7Hz, 1 H), 6.08 (br, s, 1 H), 7.03-7.23 (m, 3 H). The enantiomers wereseparated by using Chiralcel OD column (4.6×250 mm) using 80% hexane/20%isopropyl alcohol/0.1% diethylamine as the eluting system underisothermal conditions (U.V. 254 nM). The retention times for the twoisomers were 16.19 min and 20.08 min respectively. First isomer:[α]_(D)=+62.9 (c=0.67, acetone); Analysis calculated for C₉H₇NO₂F₂: C,54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Secondisomer: [α]_(D)=−56.9 (c=0.75, acetone); Analysis calculated forC₉H₇NO₂F₂: C, 54.28; H, 3.54; N, 7.03. Found: C, 54.31; H, 3.46; N,6.98. The first isomer was used in the next step.

c. (+)-2-Amino-2-(3,4-difluorophenyl)-ethanol

To a solution of (+)-4-(3,4-difluorophenyl)-oxazolidin-2-one (1.39 mmol,0.27 g) in 5.0 mL ethanol was added 5.0 mL of water and pellets ofpotassium hydroxide (5.0 mmol, 0.28 g). The resulting solution was thenheated to reflux overnight. The solvent was removed in vacuo and theresulting residue was extracted with EtOAc (2×50 mL). The organicextracts were washed with brine and the organic layer was dried overNa₂SO₄. It was filtered and the solvent was removed in vacuo to obtain(+)-2-amino-2-(3,4-difluorophenyl)-ethanol as a white solid (0.21 g, 87%yield).

This material was converted into(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester in the same manner as described in section Ipart 1g.

3. Typical Reaction for the Coupling of Side Chains (RNH₂) WithActivated Morpholinones (Schemes 1 and 2) Synthesis of(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-amide(Compound 1)

a. 4-(5-Fluoro-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride

To a 100 mL round bottom flask equipped with a rubber septum and astirring bar was added 4-hydroxy-4-phenyl-piperidine (1.25 g, 7.0 mmol)followed by 10 mL of 4-fluoroanisole. The resulting solution was stirredat room temperature under argon atmosphere and AlCl₃ (2.82 g, 21.0 mmol)was added in one portion. An exotherm was observed. The reaction mixturewas stirred for 8 hours and then poured carefully over 150 ml ofice-water. The white solid that precipitated out was filtered and washedthoroughly with water followed by diethyl ether to obtain4-(5-fluoro-2-methoxy)-phenyl-4-phenyl-piperidine hydrochloride (1.59 g,50%) as a white solid.

b. 3-[4-(2-methoxy-5-fluoro)phenyl-4-phenyl-piperidin-1-yl]propylamine

To a solution of 4-(5-fluoro-2-methoxy)-phenyl-4-phenyl-piperidine (0.6g, 2.1 mmol) in 30 mL dioxane was added3-bromo-N-tert-butoxycarbonyl-propylamine (0.6 g, 2.5 mmol) and K₂CO₃(0.6 g, 6.0 mmol) and the resulting suspension was heated to reflux for10 hours. The suspension was allowed to cool, filtered, and the solventwas evaporated to obtain yellow residue which was purified by columnchromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]-N-tert-butoxycarbonyl-propylamineas a yellow oil (0.35 g). This was dissolved in 15 mL of CH₂Cl₂ and 3.0mL of trifluoroacetic acid was added with stirring at room temperatureunder argon atmosphere for 1 hour. The solvent was evaporated in vacuoand the residue was basified to pH 10 by adding minimum amount of 1 NKOH solution. The product was extracted with CH₂Cl₂ (3×25 mL), driedover MgSO4, filtered, and the solvent was removed in vacuo to obtain3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]propylamine as ayellow oil (0.25 g, 35% for two steps). It was used in the next stepwithout further purification.

c. (+)-3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-amide(Compound 1)

To a solution of(+)-3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (0.05 g, 0.13 mmol) in 5 mL THF was added3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl)-propylamine(0.06 g) in one portion and the resulting mixture was stirred at roomtemperature overnight. The solvent was removed in vacuo and the residuewas passed through a short silica gel column with 1: hexane/EtOAcfollowed by 10% MeOH/EtOAc as the eluting system.3-(3,4-Difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5-fluoro-2-methoxyphenyl)-4-phenyl-piperidin-1-yl}-propyl}-amidewas obtained as a colorless oil (0.05 g). It was dissolved in 4 mL ofCHCl₃ and then treated with 1 mL of 1N HCl in diethyl ether to obtainits HCl salt. White solid. M.P.=110-113° C.; [α]_(D)=+25.3 (c=0.14,MeOH); Analysis calculated for C₃₂H₃₅N₃O₄F₃Cl.1.1 CHCl₃: C, 53.05; H,4.86; N, 5.61. Found: C, 53.24; H, 5.06; N, 5.44.

4. Morpholinone Example: The Synthesis of(+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide(Compound 2)

a. 1-Benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol

To a cooled solution of n-BuLi (6.0 mL, 15.0 mmol) in 20 mL THF wasadded 2-bromo-5-fluoro toluene (1.9 mL, 15.0 mmol) dropwise at −78° C.over 15 min. The reaction mixture was allowed to warm to 0° C. over 1hour and was then cooled to −78° C. 1-Benzyl-4-piperidone (1.48 mL, 8.0mmol) was added to the white slurry and the reaction mixture was warmedto 0° C. over 2 hours. The reaction was quenched with 10 mL of saturatedNH₄Cl solution. The organic layer was extracted with diethyl ether (2×50mL) and the combined organic layers were washed with brine (100 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, and thesolvent was removed in vacuo to obtain a yellow oil. It was purified bycolumn chromatography over silica gel with 3:2 hexane-EtOAc as theeluting system to obtain1-benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol as a yellow thickoil (1.1 g, 46% yield).

b. 1-Benzyl-4-(4-Fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine

To a solution of 1-benzyl-4-(5-fluoro-2-methyl)-phenyl-4-piperidinol(1.1 g, 3.68 mmol) in 100 mL toluene was added p-toluenesulfonic acidmonohydrate (1.39 g, 7.35 mmol) and the resulting solution was heated toreflux for 8 hours. The suspension was cooled and the basified with 10%KOH solution and extracted with EtOAc (2×50 mL). The organic layer waswashed with brine (30 mL). The organic layer was separated, dried overNa₂SO₄, filtered, and the solvent was removed in vacuo to obtain1-benzyl-4-(4-fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine as apale yellow oil (0.9 g, 87% yield). It was used in the next step withoutfurther purification.

c. 4-(4-Fluoro-2-methyl)-phenyl-piperidine

To a cooled suspension of 10% Pd-C (0.1 g) in 10 mL methanol was added asolution of1-benzyl-4-(4-fluoro-2-methyl)-phenyl-1,2,3,6-tetrahydropyridine (0.9 g,3.2 mmol) in 20 mL of methanol and the resulting suspension washydrogenated at room temperature under 1 atm of hydrogen for 10 hours.The suspension was filtered through a pad of celite and the solvent wasremoved from the filtrate to obtain4-(4-fluoro-2-methyl)phenyl-piperidine which was converted into itshydrochloride salt (0.62 g, 99% yield). It was used in the next stepwithout further purification.

d. (+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide(Compound 2)

4-(4-Fluoro-2-methyl)-phenyl-piperidine was converted into3-amino-propyl-4-(4-fluoro-2-methyl)phenyl-piperidine by the same manneras described in section I, part 3b. This was further converted into(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methyl)phenyl piperidin-1-yl]-propyl}-amide bythe same manner as described in section I part 3c. White solid.M.P.=92-96° C.; [α]_(D)=+19.1 (c=0.12, MeOH); Analysis calculated forC₂₆H₃₁N₃O₃F₃Cl.0.5 CHCl₃: C, 54.35; H, 5.42; N, 7.17. Found: C, 54.20;H, 5.5l; N, 6.81.

5. Morpholinone Example: The Synthesis of(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide (Compound 3)

a. 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine

To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of2.0 M solution) in 150.0 mL THF at 0° C. was added 1-benzyl-4-piperidone(55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred underargon atmosphere for 1.5 hours and then quenched with 100.0 mL ofsaturated NH₄Cl solution. The organic layer was separated and theaqueous layer was extracted with 100.0 mL of Et₂O. The combined organicextracts were washed with brine, separated, and dried over Na₂SO₄. Thesolution was filtered and the solvent was removed in vacuo to obtain ayellow oil which was purified by passing through a silica gel columnwith 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as the elutingsystem. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol was obtained as apale yellow oil in 89% yield (13.9 g). It was dissolved in 150.0 mL oftoluene and p-toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) wasadded. The resulting suspension was heated to reflux for 8 hours. Afterthe suspension was cooled, it was basified with 3 N NaOH solution andwas extracted with Et₂O (2×50 mL). The organic extracts were combined,washed with brine, and the organic layer was dried over Na₂SO₄. Thesolvent was removed in vacuo to obtain1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine as a yellowviscous oil (12.0 g, 92% yield) which was used in the next step withoutfurther purification.

b. 4-(4-fluoro)-phenyl-piperidine

To a solution of1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine (45.0 mmol,12.0 g) in 100 mL MeOH was added 1.0 g of Pd(OH)₂ and the resultingsuspension was hydrogenated under 200 psi of H₂ in a stainless steelbomb for two days. The suspension was passed through a pad of celite andthe filtrate was concentrated in vacuo to obtain4-(4-fluoro)-phenyl-piperidine (7.5 g, 94%) as a viscous oil.

c. (+)-3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide (Compound 3)4-(4-Fluoro)-phenyl-piperidine was converted into3-[4-(4-fluoro-phenyl)-piperidin-1-yl]-propylamine in the same manner asdescribed in section I part 3b. This was further converted into(+)-3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide by the samemanner described section I part 3c. White solid. M.P.=86-90° C.;[α]_(D)=+22.7 (c=0.23, MeOH); Analysis calculated for C₂₅H₂₉N₃O₃F₃Cl.0.4CHCl₃: C, 54.51; H, 5.29; N, 7.51. Found: C, 54.74; H, 5.48; N, 7.26.

6.Morpholinone Example:3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide(Compound 4)

a. 1-(2-carboxamidophenyl)piperazine

Concentrated sulfuric acid (15 mL) was added to1-(2-cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a round bottomflask, and the resulting slurry was stirred at room temperature for 48hours. The reaction mixture was poured on crushed ice very slowly andthen basified (pH 9) with 50% solution of NaOH. The aqueous layer wasextracted several times with EtOAc, dried over K₂CO₃, filtered, and thesolvent was evaporated. 1-(2-carboxamidophenyl)piperazine was obtainedas an off-white solid (1.2 g, 73%).

b. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carboxamido)-phenyl-piperiazin-1-yl]-propyl}-amide(Compound 4)

1-(2-carboxamidophenyl)piperazine was converted into1-(3-amino-propyl)-4-(2-carboxamido)-phenyl-piperazine in the samemanner as described in section I part 3b. This was further convertedinto 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carboxamido)-phenyl- piperiazin-1-yl]-propyl}-amide in thesame manner as described in section I part 3c. Pale yellow powder. M.P.118-122° C.; Analysis calculated for C₂₅H₃₀N₅O₄F₂Cl.1.1 hexane: C,59.98; H, 7.23; N, 11.07. Found: C, 60.20; H, 7.50; N, 11.32.

7. Morpholinone Example: Synthesis of3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicAcid-{3-[4-(2-nitro)-phenyl-piperazin-1-yl)propyl}-amide (Compound 5)

a. 1-(2-nitrophenyl)-piperazine

A heterogenous reaction mixture containing 2-bromonitrobenzene (2.02 g,10.0 mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100° C. for10 hours. The orange-red solid was extracted with ethyl acetate andwashed thoroughly with 3 N NaOH solution followed by brine. The organiclayer was separated and dried over Na₂SO₄, filtered and the solvent wasremoved in vacuo. The resulting red oil was purified by columnchromatography on silica gel (1:1 hexane/EtOAc followed by 4:1EtOAc/MeOH) to yield 1-(2-nitrophenyl)piperazine as an orange-red oil(1.90 g, 92%). It was characterized as a hydrochloride salt. Analysiscalculated for C₁₀H₁₄N₃O₂Cl.0.10. CHCl₃: C, 47.46; H. 5.56; N, 16.44.Found: C, 47.63; H. 5.69; N, 16.42.

b. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-nitro)-phenyl-piperazin-1-yl]-propyl}-amide (Compound 5)

1-(2-nitrophenyl)-piperazine was converted into1-(3-amino-propyl)-4-(2-nitrophenyl)-phenyl-piperazine in the samemanner as described in section I part 3b. This was further convertedinto 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-nitro)-phenyl-piperiazin-1-yl)-propyl}-amide in the samemanner as described in section I part 3c. Pale yellow sticky solid.M.P.=68-72° C.; Mass spec. 504 (M+1, 100%); Analysis calculated forC₂₄H₂₈N₅O₅F₂Cl.1.2 hexane: C, 58.25; H, 7.02; N, 10.89. Found: C, 58.39;H, 7.02; N, 10.13.

8. Morpholinone Example:3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-methyl)phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}amide(Compound 6)

a. 4-(4-Methyl)-phenyl-4-(2-methyl)phenyl piperidine hydrochloride

To a 100 mL round bottom flask equipped with a rubber septum and astirring bar was added 4-hydroxy-4-(4-methyl)phenyl-piperidine (1.25 g,6.54 mmol) followed by 20 mL of anhydrous toluene. The resultingsolution was stirred at room temperature under argon atmosphere and thenAlCl₃ (1.4 g, 10.2 mmol) was added in one portion. An exotherm wasobserved. The reaction mixture was stirred for 10 hours and then pouredcarefully over 100 ml of ice-water. The white solid that precipitatedout was filtered and washed thoroughly with water followed by diethylether to obtain 4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidinehydrochloride (1.95 g, 99%) as a white solid. Mass spectrum: 266 (M+1,100%). Analysis calculated for C₁₉H₂₄NCl 0.15 CH₂Cl₂: C, 73.11; H, 7.79;N, 4.45. Found: C, 73.33; H, 7.82; N, 3.92.

b. 3-[4-(4-methyl-phenyl-4-(2-methyl)phenyl piperidin-1-yl]propylamine

To a solution of 4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidinehydrochloride (2.6 g, 9.8 mmol) in 100 mL dioxane was added3-bromo-N-tert-butoxycarbonylpropylamine (2.57 g, 10.8 mmol) and K₂CO₃(4.06 g, 29.4 mmol) and the resulting suspension was heated to refluxfor 10 hours. The suspension was allowed to cool, filtered, and thesolvent was evaporated to obtain a yellow residue which was purified bycolumn chromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain3-[4-(4-methyl-phenyl-4-(2-methyl)phenylpiperidin-1-yl]-N-tert-butoxycarbonyl-propylamine as a yellow oil (2.30g). It was dissolved in 60 mL of CH₂Cl₂ and 10.0 mL of trifluoroaceticacid was added with stirring at room temperature under argon atmospherefor 1 hour. The solvent was evaporated in vacuo and the residue wasbasified to pH 10 by adding minimum amount of 1 N KOH solution. Theproduct was extracted with CH₂Cl₂ (3×25 mL), dried over MgSO4, filtered,and the solvent was removed in vacuo to obtain3-[4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidin-1-yl]propylamine asa yellow oil (1.39 g, 44% for two steps).

c. 3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)phenyl-piperidin-1-yl]-propyl}-amide(Compound 6)

3-[4-(4-methyl-phenyl-4-(2-methyl)phenyl piperidin-1-yl]propylamine wasconverted into 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-methyl)-phenyl-4-(4-methyl)-phenyl-piperidin-1-yl]-propyl}-amidein the same manner as described in section I part 3c. Yellow stickysolid.; Mass spec. 562 (M+1, 100%); Analysis calculated forC₃₃H₃₈N₃O₃F₂Cl.0.75 CH₂Cl₂: C, 61.25; H, 6.02; N. 6.35. Found: C, 61.07;H, 6.46; N, 5.95.

9. Morpholinone Example: The Synthesis of3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethyl}]-amide (Compound 7)

A general procedure was utilized to form3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethylamine. A mixture of4-cyano-4-aryl-cyclohexanone (48.7 mmol) and ethylenediamine (8.78 g,146 mmol) and p-toluenesulfonic acid (92 mg) in benzene (200 mL) wasrefluxed for 4 hour with Dean-Stark trap to remove the water thatformed. Solvent was evaporated and the residue was redissolved inmethanol (60 mL) and cooled to 0° C. Sodium borohydride (6.45 g) wasadded in portions and the mixture was stirred at room temperature for 3hours. Solvent was evaporated, the residue was dissolved indichloromethane (300 mL), washed with brine (3×500 mL), dried (potassiumcarbonate), and the solvent evaporated to leave the product as a paleyellow viscous oil (90-95%). The product was found to contain thecis/trans isomers in a ratio of about 9:1. Careful chromatography ofthis mixture with chloroform/methanol/2 M ammonia in methanol (100/10/5to 100/20/10) yielded several earlier fractions enriched in trans isomerwith respect to the amino and cyano groups. Later fractions elutedcontained almost pure cis isomer relative to the amino and cyano groups.3-[4-cyano-4-(phenyl)cyclohex-1-yl]ethylamine was converted to3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-cyano-4-(phenyl)cyclohex-1-yl]-ethyl}]-amide in the samemanner as described in section I part 3c. Yellow powder.; M.P.=85-89°C.; Analysis calculated for C₂₆H₂₉N₄O₃F₂Cl1.0 CH₂Cl₂: C, 53.70; H, 5.17;N, 9.28. Found: C, 53.78; H, 5.30; N. 8.87.

10. Morpholinone Example: The Synthesis of3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide(Compound 8)

a. 1-(2-carbomethoxyphenyl)-piperazine

To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in1,6-dioxane (100 ml) at room temperature was added piperazine (15.3 g,178 mmol) and K₂CO₃ (4.92 g, 35 mmol). The resulting mixture was heatedto reflux for 7 days after which the reaction mixture was cooled to roomtemperature. The solvent and the excess piperazine were removed in vacuoalong with heating with a hot water bath. The residue was dissolved in1N NaOH solution, extracted with CH₂Cl₂ (6×30 ml), and dried overNa₂SO₄. The solvent was removed in vacuo to obtain1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g, 26%).

b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide(Compound 8)

1-(2-Carbomethoxyphenyl)-piperazine was converted into1-(3-amino-propyl)-4-(2-carbomethoxyphenyl)-piperazine in the samemanner as described in section I part 3b. This was further convertedinto 3-(3,4-difluorophenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(2-carbomethoxy-phenyl-piperazin-1-yl]-propyl}-amide in thesame manner as described in section I, part 3c. Yellow hygroscopicsolid; Analysis calculated for C₂₆H₃₂N₄O₅F₂Cl₂.0.3 CH₂Cl₂: C, 51.37; H,5.34; N, 9.11. Found: C, 51.16; H, 5.37; N. 8.27.

11. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide (Compound9)

a. 3-[4-Carbomethoxy-4-phenyl-piperidin-1-yl]-ethylamide

To a solution of 4-carbomethoxy-4-phenyl-piperidine (0.4 g, 2.1 mmol) in30 mL dioxane was added 3-bromo-N-tert-butoxycarbonyl-ethylamine (0.5 g,2.5 mmol) and K₂CO₃ (0.6 g, 6.0 mmol) and the resulting suspension washeated to reflux for 10 hours. The suspension was allowed to cool, wasfiltered, and the solvent was evaporated to obtain a yellow residuewhich was purified by column chromatography (Rf=0.4, 3:1 EtOAc/MeOH) toobtain3-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-N-tert-butoxycarbonyl-ethylamineas a yellow oil (0.35 g). It was dissolved in 15 mL of CH₂Cl₂ and 3.0 mLof trifluoroacetic acid was added with stirring at room temperatureunder argon atmosphere for 1 hours. The solvent was evaporated in vacuoand the residue was basified to pH 10 by adding minimum amount of 1 NKOH solution. The product was extracted with CH₂Cl₂ (3×25 mL), driedover MgSO4, filtered and the solvent was removed in vacuo to obtain3-[4-carbomethoxy-4-phenyl-piperidin-1-yl]ethylamine as a yellow oil(0.25 g, 55% for two steps). Yellow solid; M.P.=113-117° C.; Analysiscalculated for C₂₆H₃₀N₃O₅F₂Cl.0.3 Et₂O: C, 58.32; H, 6.14; N, 6.81.Found: C, 58.31; H, 5.94; N. 7.50.

b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide (Compound9)

3-[4-Carbomethoxy-4-phenyl-piperidin-1-yl]-ethylamine was converted into3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{2-[4-carbomethoxy-4-phenyl-piperidin-1-yl]-ethyl}-amide in thesame manner as described in section I, part 3c. Yellow solid;M.P.=113-117° C.; Analysis calculated for C₂₆H₃₀N₃O₅F₂Cl.0.3 Et₂O: C,58.32; H, 6.14; N, 6.81. Found: C, 58.31; H, 5.94; N, 7.50.

12. Morpholinone Example: Synthesis of3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}amide (Compound 10)

a. 3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine

3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine was synthesized fromcommercially available 4-hydroxy-4-phenyl piperidine using the sameprocedure as described in section I, part 3b.

b. 3-(3,4-Difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide (Compound 10)

3-[4-Hydroxy-4-phenyl-piperidin-1-yl]-propylamine was converted into3-(3,4-difluoro-phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-hydroxy-4-phenyl-piperidin-1-yl]-propyl}-amide in the samemanner as described in section I, part 3c. Yellow solid.; M.P.=85-88°C.; Analysis calculated for C₂₅H₃₀N₃O₄F₂Cl.0.2 MeOH: C, 58.61; H, 6.01;N, 8.14. Found: C, 58.29; H, 6.42; N, 7.98.

13. (−)-3-Phenyl)-5-oxo-morpholine-4-carboxylicacid-{3-[4-(5′-fluoro-2′-methoxy)phenyl-4-phenyl-piperidin-1-yl]-propyl}-amide(Compound 11)

3-Phenyl-5-oxo-morpholine-4-carboxylic acid-4-nitro-phenyl ester wasprepared from R-(−)-phenyl glycinol in the same manner as described insection I, parts 1d-g. It was coupled with3-[4-(5-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl)-propylamine(section I parts 3a-b) in the same manner as described in section I,part 3c. White powder. M.P.=105-109° C.; [α]_(D)=−49.0 (c=0.12, MeOH)Analysis calculated for C₃₂H₃₇N₃O₄F₂Cl.1.0 CH₂Cl₂: C, 59.42; H, 5.89; N,6.30. Found: C, 59.51; H, 6.22; N, 6.05.

II. Synthesis of Substituted Morpholinone Examples 1. Synthesis of3-(3,4-difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (Scheme 3)

a. 2-Hydroxy-1-pyrrolidin-1-yl-propan-1-one

The procedure has been reported (Vilarrasa et al., Tetrahedron Lett. 38,1633, 1997). S-(+)-Methyl lactate (48.03 mmol, 5.0 g) and pyrrolidine(52.8 mmol, 4.4 mL) were mixed in a round bottom flask and the reactionmixture was allowed to stir at room temperature for four days. Methanolwas distilled off using a short path distillation apparatus to obtain2-hydroxy-1-pyrrolidin-1-yl-propan-1-one as a yellow oil. It was used inthe next reaction without further purification.

b. 2-(tert-Butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one

To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one (47.0 mmol,6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g),N,N-dimethyl-4-aminopyridine (4.7 mmol, 0.57 g) at room temperature.tert-Butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g) was then addedwhile stirring. Some exotherm was observed. The initial pale yellowsolution turned brown-red in color and some precipitate was observedafter 30 min. The reaction mixture was stirred overnight and was thenfiltered through a sintered glass funnel. The solid was washed withEt₂O. The filtrate was diluted with water (150 mL) and it was extractedwith Et₂O (2×100 mL). The organic extracts were combined and washedsuccessively with water (100 mL), saturated NH₄Cl solution, and theorganic layer was separated. It was dried over Na₂SO₄, filtered, and thesolvent was removed in vacuo to obtain2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one as agolden yellow oil (10.4 g, 86% yield). The product was judged to be >95%pure by NMR and was used in next step without any purification.

c.2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluorophenyl)-1-yl-propan-1-one

To a round bottom flask containing 72.0 mL of THF at −78° C. was added asolution of n-butyllithium in hexane (72.0 mmol, 45.0 mL) under an argonatmosphere followed by 1-bromo-3,4-difluorobenzene (72.0 mmol, 8.1 mL).A solution of2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one (60.0mmol, 15.4 g) in 10.0 mL THF was then added in a steady stream and theorange colored solution was stirred for 35 min at −78° C. It wasquenched with 20.0 mL of saturated NH₄Cl solution and was allowed toattain room temperature. The solution was extracted with Et₂O (2×50 mL),washed with brine, and the organic layer was dried over Na₂SO₄. Thesolution was filtered, and the solvent was removed in vacuo to obtainthe product as an orange oil. The crude product was subjected to silicagel flash column chromatography (9:1 hexane/EtOAc to 4:1 hexane/EtOAc asthe eluent system).2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-onewas obtained as a pale yellow oil (14.1 g, 78% yield, 96% based on therecovered starting material).

d.2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluorophenyl)-1-yl-propan-1-one-oxime

To a solution of2-(tert-butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one(13.7 mmol, 4.1 g) in 60.0 mL of methanol was added sodium acetate (3.76g) and hydroxylamine hydrochloride (1.24 g) and the resulting solutionwas stirred at room temperature overnight. Methanol was then removed invacuo and the resulting residue was extracted with EtOAc (2×50 mL) andbrine. The organic layer was separated, dried over Na₂SO₄, filtered, andthe solvent was removed in vacuo.2-(tert-Butyl-dimethyl-silanyloxy)-1-(3,4-difluorophenyl)-1-yl-propan-1-one-oximewas obtained as a colorless oil (4.04 g, 94% yield) and was used in thenext step without further purification.

e. 1-Amino-1-(3,4-difluorophenyl)-propan-2-ol

To a solution of2-(tert-butyl-dimethyl-silanyloxy)-1-(3,4-difluoro-phenyl)-1-yl-propan-1-one-oxime(12.2 mmol, 3.84 g) in 20.0 mL of Et₂O was added a 1.0 M solution oflithium aluminum hydride (25.0 mmol, 25.0 mL) at 0° C. under an argonatmosphere. After 1 hour, the solution was heated to reflux for 2 hoursat which time some solid was observed. The reaction mixture was cooledto 0° C. and then quenched sequentially with water (1.0 mL), 1.0 N KOH(1.0 mL), and water (3.0 mL). The residue was filtered and the solid waswashed with warm Et₂O (20.0 mL). The filtrates were combined and driedover Na₂SO₄. The solution was filtered and the solvent was removed invacuo to obtain 1-amino-1-(3,4-difluorophenyl)-propan-2-ol as acolorless oil which solidified into a low melting solid (2.1 g, 92%yield). It was used in the next step without purification.

f. 3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester

1-Amino-1-(3,4-difluorophenyl)-propan-2-ol was converted to3-(3,4-difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester in the same manner as described in section I,parts 1d-g or 2.

2. Substituted Morpholinone Example:(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propyl}-amide (Compound 12)

3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (section II part 1) was coupled to3-[4-(4-fluoro)phenyl-piperidin-1-yl]-propylamine (section I part 5) inthe same manner as described in section I, part 3c. Yellow hygroscopicsolid. M.P.=69-73° C.; Mass spec. 490 (M+1, 100%); [α]_(D)=+20.2(c=0.08, MeOH). Analysis calculated for C₂₆H₃₁N₃O₃F₂Cl.2.0 H₂O: C,57.51; H, 6.50; N, 7.74. Found: C, 57.61; H, 6.15; N, 7.27.

3. Substituted Morpholinone Example:(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-{3-[4-(4-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]-propyl}-amide(Compound 13)

3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (section II part 1) was coupled to3-[4-(4-fluoro-2-methoxy)phenyl-4-phenyl-piperidin-1-yl]-propylamine(section I, part 3a-b) in the same manner as described in section I,part 3c. Yellow powder. M.P.=95-99° C.; Mass spec. 596 (M+1, 100%);[α]_(D)=+56.9 (c=0.13, MeOH) Analysis calculated for C₃₃H₃₆N₃O₄F₂Cl.1.5CH₂Cl₂: C, 54.56; H, 5.31; N, 5.53. Found: C, 54.51; H, 5.63; N, 5.20.

4. Substituted Morpholinone Example:(+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-{3-[4-(cyano-4-phenyl-piperidin-1-yl]-propyl}-amide (Compound 14)

a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthalimide

A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol),3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate(276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirredand heated at 100-110° C. for 8 hours. About 80% of the solvent wasevaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96-98° C.

b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl) propylphthalimide(112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added andthe mixture was stirred and refluxed for 20 hours. It was cooled, thewhite solid formed was filtered and washed with more methanol (200 mL).Solvent was evaporated from the filtrate and residue was dried undervacuum for 4 hours. Chloroform (500 mL) was added to this, stirred for 1hour and filtered. The white solid was washed with more chloroform (200mL), the solvent was evaporated from the combined filtrates to leave theproduct as an oil (70 g, 96%).

c. (+)-3-(3,4-Difluoro-phenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-{3-[4-(cyano-4-phenyl-piperidin-1-yl]-propyl}-amide

3-(3,4-Difluorophenyl)-2-methyl-5-oxo-morpholine-4-carboxylicacid-4-nitro-phenyl ester (section II, part 1) was coupled to3-[4-(cyano-4-phenyl-piperidin-1-yl]-propylamine in the same manner asdescribed in section I, part 3c. White powder. M.P.=191-194° C.; Massspec. 497 (M+1, 100%); [α]_(D)=+23.1 (c=0.09, MeOH) Analysis calculatedfor C₃₃H₃₆N₃O₄F₂Cl.0.35 CH₂Cl₂: C, 58.38; H, 5.68; N, 9.96. Found: C,58.57; H, 6.03; N, 9.72.

III. Synthesis of Substituted Morpholinone Examples (Schemes 4a and4b) 1. Synthesis of (+)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (Scheme4a)

a. Amino-(3,4,-difluorophenyl)-acetonitrile

Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.18 mol) inMeOH (500 mL) in a round bottom flask was bubbled ammonia gas for twohours at room temperature. The flask was then cooled to 0° C. andtrimethylsilyl cyanide (1.3 eq., 0.23 mmol) was then added slowly. Thereaction mixture was stirred for 2 hours when TLC analysis indicted thatthe reaction was complete (R_(f)=0.35, 3:2 hexane/EtOAc). Solvent wasremoved in vacuo and the residue was subjected to flash columnchromatography on silica gel to obtain 25.0 g (81%) ofamino-(3,4-difluorophenyl)-acetonitrile as a yellow syrup.

b. Methyl 2-amino-2-(3,4-difluorophenyl)acetate

To a well stirred solution of amino-(3,4-difluorophenyl)-acetonitrile(22.0 g., 0.130 mol), a solution of HCl in MeOH (200 mL) was added atroom temperature. The resulting yellow solution was stirred at roomtemperature for 10 hours and then heated to reflux for 1.5 hours. Aftercooling, the solvent was removed in vacuo and the resulting yellow solidwas dissolved in water (200 mL). The aqueous solution was then carefullybasified with 20% NaOH solution to pH 9. The aqueous layer was extractedwith CH₂Cl₂ (3×100 mL). The organic layer was separated and dried overNa₂SO₄, filtered and the solvent was removed in vacuo to obtain 22.2 g(84%) of methyl 2-amino-2-(3,4-difluorophenyl)acetate as a brownishyellow liquid. It was used in the next step without purification.

c. (+)-1-(3,4-Difluorophenyl)-2,2-dimethyl-2-hydroxypropylamine

To a well-stirred solution of methyl2-amino-2-(3,4-difluorophenyl)acetate (10.5 g, 52.19 mmol) in anhydrousether (200 mL) at 0° C. was added a solution of methylmagnesium bromidein ether (3 M, 87 mL, 261 mmol) over 10 minutes. The mixture was stirredat 0° C. for 2.5 hours and allowed to warm to room temperature. After 12hours, the mixture was carefully poured onto a mixture of ice (300 g)and saturated ammonium chloride (50 g). The ether layer was separatedand the aqueous layer was extracted with more ether (4×200 mL). Thecombined extracts were dried over magnesium sulfate and the solventevaporated. The crude product was purified by column chromatography onsilica gel using chloroform/methanol/2M ammonia in methanol(1000:20:10/1000:40:20, 1000:80:40) as eluents to give the product as anoil (6.5 g, 62%). The ¹H-NMR and MS confirmed this to be the desiredproduct.

d. (+)-1-(3,4-Difluorophenyl)-2,2-dimethyl-2-hydroxypropylaminechloroacetamide

To a solution of1-(3,4-difluorophenyl)-2,2-dimethyl-2-hydroxypropylamine (10.20 g, 50.70mmol) and triethylamine (5.0 mL) in dichloromethane (100 mL) at −78° C.was added chloroacetyl chloride (4.64 mL, 60.83 mmol) dropwise over 10min. The resulting mixture was stirred at −78° C. for 2 hours and wasthen slowly warmed to −40° C. over one hour. The reaction was quenchedby adding H₂O (20 mL) and the mixture was extracted with EtOAc (2×100mL). The ethyl acetate extracts were dried over MgSO₄ and concentratedto a residue which was purified by column chromatography (SiO₂, 30% to50% EtOAc/Hex) to afford the product as a colorless oil (6.50 g, 46 %yield).

e. (+)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine

Lithium bis(trimethylsilyl)amide (5.68 mL, 1.0 M in THF) was added to astirred solution of 1-(3,4-difluorophenyl)-2-methyl-2-hydroxypropylamine2-chloroacetamide (1.21 g, 4.37 mmol) in THF at 0° C. The resultingmixture was stirred while warmed to room temperature over 30 min. It wasthen heated to 50° C. and stirred for 60 min. The mixture was quenchedwith water (2 mL) and extracted with EtOAc (2×100 mL). The extracts weredried (Na₂SO₄) and the solvent was evaporated. The crude product waspurified by column chromatography (SiO₂, 50:50 to 90:10 EtOAc/Hexanes)to give 0.36 g (34%) of morpholinone as a pale yellow oil.

f (+)-4-Nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate

To a solution of(+)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine (240 mg, 0.996mmol) in THF (10 mL) at −78° C. was added lithiumbis(trimethylsilyl)amide (1.10 mL, 1.0 M in THF). The mixture wasstirred for 30 min at 0° C. and then cooled back to −78° C. The mixturewas transferred via a cannula to a precooled solution of 4-nitrophenylchloroformate (605 mg, 3.0 mmol) in THF (10 mL) at −78° C. The resultingmixture was stirred while warmed to room temperature over 3 hours. Thereaction was quenched with water (2 mL) and extracted with EtOAc (2×100mL). The organic layer was dried with Na₂SO₄ and the solvent wasevaporated. The residue was purified by column chromatography (SiO₂,40:60 EtOAc/Hexanes) to afford 0.328 g (81%) of the product as a paleoil.

2. Synthesis of Enantiomerically Pure 4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (Scheme4b)

a. (S)-(+)-O-Acetylmandelyl(±)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine-3-amide

To a solution of (S)-(+)-O-acetylmandelic acid (408 mg, 2.10 mmol) inEt₂O (50 mL) and triethylamine (212 mg) under argon at −78° C., wasadded 2,2,2-trimethylacetyl chloride (272 mg, 2.10 mmol). The resultingmixture was warmed to 0° C. in ice-bath for 10 min to yield the acidchloride and it was then cooled back to −78° C. At the same time,(±)-2,2-dimethyl-3-(3,4-difluorophenyl)-6-oxo-morpholine (406 mg, 1.68mmol) was dissolved in THF (15 mL) in another dried flask and cooled to−78° C., and n-BuLi (0.75 mL, 2.5 M) was added dropwise. The resultingsolution was stirred for 10 min and was then transferred to the acidchloride via a cannula. The reaction mixture was stirred for 10 min at−78° C. and was then warmed to 0° C. and stirred for 1 hour beforequenching with water (2 mL). The mixture was extracted with EtOAc (2×50mL), dried (Na₂SO₄), and the solvent was evaporated. The crude productwas purified by column chromatography (SiO₂, 15:85 to 30:70EtOAc/Hexanes) to obtain 0.476 g of the two diastereomers as purecompounds. (combined yield: 68%) (Higher R_(f) product: 318 mg; Lower Rfproduct: 158 mg).

b. (−)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine

LiOH.H₂O (281 mg, 6.71 mmol) was added to a solution of the amide fromthe previous step (Higher R_(f) compound, 280 mg, 0.671 mmol) in THF (20mL), H₂O (2 mL) and H₂O₂ (5 mL). The resulting mixture was stirredvigorously for one hour. The mixture was filtered and the filtrate wasextracted with EtOAc (2×50 mL), dried (Na₂SO₄), and the solvent wasevaporated. The crude product was purified by column chromatography(SiO₂, 50:50 to 90:10 EtOAc/Hexanes) (0.120 g, 74%). optical rotation[α]_(D)=−10.0 (c 4.5, MeOH).

c. (+)-2,2-Dimethyl-3-(3,4-difluorophenyl)-5-oxomorpholine

Prepared in the same manner as described in section III, part 2b from150 mg of amide (lower R_(f) compound). Yield: 65 mg (75%); [α]_(D)=+9.6(c=2.5, MeOH)

d. Enantiomerically pure 4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate

The enantiomerically pure4-nitrophenyl-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylateswere prepared from(−)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine and(+)-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholine in a similarmanner as described in section III, part 1d.

3. Typical Reaction Sequence for the Coupling of Side Chains (RNH₂) WithActivated Morpholinones (Scheme 4) Synthesis ofN-4-[3-(4-methoxycarbonyl-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride (Compound 15)

a. 4-Methoxycarbonyl-4-phenylpiperidine

To a stirred solution of H₂SO₄ (16 mL) in MeOH (400 mL),4-phenyl-4-piperidinecarboxylic acid 4-methyl benzenesulfonate (37.7 g,0.1 mole) was added and the mixture was stirred and refluxed for 8hours. Excess methanol was evaporated at reduced pressure and theresidue was poured into a mixture of ice and 6 N NaOH. The pH wasadjusted to 10-11 by adding more 6 N NaOH and extracted with CH₂Cl₂(3×150 mL). The combined CH₂Cl₂ extracts were dried (MgSO₄) and thesolvent evaporated to leave the desired product as a viscous oil. Theproduct (20.2 g, 92%) was used without further purification.

b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine

A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039 mol),3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate(13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200mL) was stirred and refluxed for 24 hours. Dioxane was evaporated atreduced pressure, the residue was treated with ice-cold 6 N NaOH (400mL) and extracted with CH₂Cl₂ (4×120 mL). Solvent was evaporated fromthe combined dried (K₂CO₃) extracts and the residue was purified bycolumn chromatography on silica gel using CHCl₃/MeOH/2 M NH₃ in MeOH(20:2:1) as the eluent to afford the product as a viscous oil (7.8 g,72%).

c.N-4-[3-(4-methoxycarbonyl-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

4-Methylcarboxyl-4-phenyl-piperidinyl-N-propylamine (100 mg, 0.384 mmol)was added to a stirred solution of(±)-4-nitrophenyl-2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate(15 mg, 0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirredat room temperature overnight and purified by prep. TLC on silica gelusing EtOAc as the eluent to give 10 mg product (50%). The HCl salt wasprepared by treatment with 1 N HCl in ether.

4. Substituted Morpholinone Example: Methyl4-[2-([3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxomorpholino]carbonylamino)ethyl]amino-1-phenyl-1-cyclohexanecarboxylatehydrochloride (cis isomer) (Compound 16)

a. 2-[4-Methoxycarbonyl-4-phenyl-cyclohexylamino]ethylamine

A mixture of 2-[4-cyano-4-phenylcyclohexylamino]ethylamine (2.34 g, 10mmol) and concentrated sulfuric acid (20 mL) was heated at 80-85° C. for10 hours. It was cooled to room temperature, mixed with anhydrousmethanol (200 mL), and refluxed for 20 hours. Solvent was evaporated andthe residue was poured onto ice (200 g) and basified to pH 11 byaddition of 6 N NaOH. It was extracted with dichloromethane (4×125 mL),dried (potassium carbonate) and solvent evaporated to leave the productas an oil (2.1 g, 76%). This product was a pure mixture of cis and transisomers. It was used in the next step without any further purification.

b. Methyl4-[2-([3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxomorpholino]carbonylamino)ethyl]amino-1-phenyl-1-cyclohexanecarboxylatehydrochloride (cis isomer)

4-Methylcarboxyl-4-phenyl-cyclohexyl-amino-ethylamine (25 mg, 0.091mmol) was added to a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred at RTovernight and purified by prep. TLC on silica gel using EtOAc as eluentto give 10 mg product (51%). MH⁺=544. The HCl salt was prepared bytreatment with 1 N HCl in ether.

5. Substituted Morpholinone Example:N-4-[3-{4-(2-pyridyl}piperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxanidehydrochloride (Compound 17)

a. 1-Benzyl-4-cyano-4-(2-pyridyl)piperidine

To a mixture of N,N-bis-(2-chloroethyl)benzylamine (Szarvasi, E., Eur.J. Med. Chem. Chim. Ther. 11(2), 115-124, 1976) (60 g, 22 mmol),2-pyridylacetonitrile (2.51 mL, 22 mmol) and tetrabutylammonium hydrogensulfate (0.26 g, 0.7 mmol) in toluene (10 mL), sodium hydroxide solution(2.43 g in 4.86 mL H₂O) was added over a 20 minute period. The reactionmixture was heated at 65° C. for 4 hours. The reaction mixture wascooled to room temperature, 10 mL of water was added and the solutionpartitioned between ethyl acetate (45 mL) and water. The organic layerwas dried over sodium sulfate, filtered and concentrated. Purificationof the crude product by column chromatography (hexane: EtOAc, 2:3) gave6.2 g (87 %) of the title compound as a red solid; ¹H-NMR (CDCl₃): δ2.05 (d, J=13.1 Hz, 2H), 2.30 (t, J=13.2 Hz, 2H), 2.48 (t, J=13.2 Hz, 2H), 2.97 (d, J=12.1 Hz, 2 H), 3.57 (s, 2 H), 7.19-7.27 (m, 6 H), 7.30(d, J=7.6 Hz, 1 H), 7.60 (t, J=7.6 Hz, 1 H ), 8.58 (d, J=4.6 Hz, 1 H).

b. 1-Benzyl-4-carboxamido-4-(2-pyridyl)piperidine

To 1-benzyl-4-cyano-4-(2-pyridyl) piperidine (4.5 g, 14.3 mmol), 10 mLof conc. H₂SO₄ was added and the solution was stirred at roomtemperature for 24 hours. It was cooled to 0° C., diluted with icepieces and poured into crushed ice. The mixture was then carefullyneutralized with 50% NaOH solution. The reaction mixture was repeatedlyextracted with chloroform (3×25 mL), dried over sodium sulfate, filteredand concentrated to give 4.5 g (95%) of the crude product which was usedas such for the subsequent step; ¹H-NMR (CDCl₃): δ 2.21 −2.28 (m, 2 H),2.47 (s, 6 H), 3.41 (s, 2 H), 5.23 (s, 1 H), 6.40 (s, 1 H), 7.12-7.29(m, 6 H), 7.33 (d, J=7.6 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.55 (d,J=4.6 Hz, 1 H).

c. 1-Benzyl-4-(2-pyridyl)-piperidine

To 1-benzyl-4-carboxamido-4-(2-pyridyl)piperidine (4.5 g, 13.5 mmol) inanhydrous methanol (100 mL), HCl gas was bubbled through the solution at0° C. for 15 minutes. The reaction mixture was then refluxed for 24hours. It was cooled to room temperature, concentrated, neutralized with50% NaOH and repeatedly extracted with chloroform (3×25 mL). Thecombined organic layer was then dried over sodium sulfate, filtered andconcentrated. Flash chromatography (hexane:ethylacetate, 1:4) of thecrude product yielded 1.72 g (50%) of the product as a syrup; ¹H-NMR(CDCl₃): δ 1.8-1.94 (m, 4 H), 2.11 (t, J=11.4 Hz, 2 H), 2.70-2.72 (m, 1H), 3.02 (d, J=11.4 Hz, 2 H), 3.54 (s, 2 H), 7.07-7.36 (m, 7 H), 7.58(t, J=7.6 Hz, 1 H), 8.52 (d, J=4.6 Hz, 1 H).

d. 3-[4-(2-Pyridyl)-piperidine-1-yl]propylamine

To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol(25 mL), 10% palladium hydroxide (1.9 g) was added and the solution washydrogenated at 200 psi for 24 hours. The solution was filtered overcelite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidinewhich was used as such for the subsequent step. A mixture of3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate(37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol)in methanol was stirred at room temperature for 24 hours. The reactionmixture was concentrated and partitioned between 250 mL EtOAc and 50 mLwater, dried over sodium sulfate, filtered and concentrated.Purification of the crude product by column chromatography (hexane:EtOAc, 4. 5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil.To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine(2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) wereadded and the solution was refluxed for 24 hours. The reaction mixturewas cooled to room temperature, concentrated and partitioned between 40mL chloroform and 5 mL water. The organic layer was dried over sodiumsulfate, filtered and concentrated. The crude product was purified bycolumn chromatography (ethyl acetate:methanol, 4:1) to yield 1.86 g(49%) of the required product as a colorless oil; ¹H-NMR (CDCl₃): δ 1.45(s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H),3.02-3.22 (m, 4 H), 5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). ToN-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine(0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroaceticacid was added and the solution was stirred at room temperature for 1hour. The solution was concentrated, neutralized with 10% KOH solutionand extracted into 25 mL of dichloromethane. The organic layer was driedover sodium sulfate, filtered, and concentrated to give 0.098 g (100%)of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such forthe subsequent step.

e.N-4-[3-{4-(2-pyridyl}piperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

4-(2-Pyridinyl)piperidinyl-N-propylamine (25 mg, 0.114 mmol) was addedto a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred at RTovernight and purified by prep. TLC on silica gel using EtOAc as eluentto give 10 mg product (52%). MH⁺=487. The HCl salt was prepared bytreatment with 1 N HCl in ether.

6. Substituted Morpholinone Example:N-4-[3-(4-Cyan-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamideHydrochloride (Compound 18)

a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide

A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol),3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate(276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirredand heated at 100-110° C. for 8 hours. About 80% of the solvent wasevaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96-98° C.

b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide(112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added andthe mixture was stirred and refluxed for 20 hours. It was cooled, thewhite solid formed was filtered and washed with more methanol (200 mL).Solvent was evaporated from the filtrate and residue was dried undervacuum for 4 hours. Chloroform (500 mL) was added to this, stirred for 1hour and filtered. The white solid was washed with more chloroform (200mL), the solvent was evaporated from the combined filtrates to leave theproduct as an oil (70 g, 96%).

c.N-4-[3-(4-Cyan-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

4-Cyan-4-phenyl-piperidinyl-N-propylamine (25 mg, 0.103 mmol) was addedto a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as eluent to give 10 mg product (51%). MH⁺=511. The HCl salt wasprepared by treatment with 1 N HCl in ether.

7. Substituted Morpholinone Example: (+)-N-4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamideHydrochloride (Compound 18)

a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide

A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol),3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate(276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirredand heated at 100-110° C. for 8 hours. About 80% of the solvent wasevaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96-98° C.

b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide(112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added andthe mixture was stirred and refluxed for 20 hours. It was cooled, thewhite solid formed was filtered and washed with more methanol (200 mL).Solvent was evaporated from the filtrate and residue was dried undervacuum for 4 hours. Chloroform (500 mL) was added to this, stirred for 1hour and filtered. The white solid was washed with more chloroform (200mL), the solvent was evaporated from the combined filtrates to leave theproduct as an oil (70 g, 96%).

c.(+)-N-4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

4-Cyano-4-phenyl-piperidinyl-N-propylamine (40 mg, 0.165 mmol) was addedto a stirred solution of (−)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as the eluent to give 16 mg product (85%). [α]_(D)=+26.3 (c=0.8,CH₂Cl₂). MH⁺=511. The HCl salt was prepared by treatment with 1 N HCl inether.

8. Substituted Morpholinone Example: (−)-N4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamideHydrochloride (Compound 18)

a. 3-(4-Cyano-4-phenylpiperidin-1-yl)propyl phthalimide

A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol),3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate(276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirredand heated at 100-110° C. for 8 hours. About 80% of the solvent wasevaporated at reduced pressure, the residue was diluted withdichloromethane (1 L) and washed with brine (3×300 mL) and dried(Na₂SO₄). Solvent was evaporated from the dichloromethane solution andthe residue was treated with isopropanol (400 mL) and cooled. The paleyellow crystalline product formed was filtered, washed with ice-coldisopropanol and dried (168.6 g, 90%); M.p. 96-98° C.

b. 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine

To a solution of 3-(4-cyano-4-phenylpiperidin-1-yl)propylphthalimide(112 g, 0.3 mol) in methanol (1.5 L), hydrazine (30 mL) was added andthe mixture was stirred and refluxed for 20 hours. It was cooled, thewhite solid formed was filtered and washed with more methanol (200 mL).Solvent was evaporated from the filtrate and residue was dried undervacuum for 4 hours. Chloroform (500 mL) was added to this, stirred for 1hour and filtered. The white solid was washed with more chloroform (200mL), the solvent was evaporated from the combined filtrates to leave theproduct as an oil (70 g, 96%).

c. (−)-N4-[3-(4-Cyano-4-phenylpiperidino)propyl]-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamidehydrochloride

4-Cyano-4-phenyl-piperidinyl-N-propylamine (40 mg, 0.165 mmol) was addedto a stirred solution of (+)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂(5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC with EtOAc as eluent togive 14 mg product (74%). [α]_(D)=−25.7 (c=0.7, CH₂Cl₂). MH⁺=511. TheHCl salt was prepared by treatment with 1 N HCl in ether.

9. Substituted Morpholinone Example:3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxylicacid-{2-[4-(2-pyridyl)piperidin-1-yl]-1-methyl-ethyl}-amideHydrochloride (Compound 19)

a. N-(tert-Butoxycarbonyl)-L-alanine 4-(2-pyridyl)piperidin-1-yl amide

To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.485 g, 7.847 mmol)and 4-(2-pyridyl)piperidine (0.910 g, 5.60 mmol) in dichloromethane (20mL) at 0° C., was added N,N-dimethylaminopyridine (DMAP, 2.05 g, 16.8mmol) and 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride(DMAPECD, 2.147 g, 11.2 mmol). The resulting mixture was stirredovernight while warmed up to room temperature. The reaction mixture wasquenched with aqueous NH₄Cl (30 mL) and extracted with CH₂Cl₂ (30 mL×2).The combined extracts were dried (K₂CO₃), concentrated, and purified byflash chromatography on silica gel (100% EtOAc) to obtain 2.09 g (80%)of N-(tert-Butoxycarbonyl)-L-alanine 4-(2-pyridyl)piperidin-1-yl amide.

b.(S)-N-(tert-Butoxycarbonyl)amino-3-[4-(2-pyridyl)piperidin-1-yl]propane

To a solution of N-(tert-butoxycarbonyl)-L-alanine4-(2-pyridyl)piperidin-1-yl amide (0.650 g, 1.95 mmol) in THF (20 mL) at0° C. was added LAH (4.0 mL, 1.0 M in THF) dropwise. The resultingmixture was stirred for 3 hours before quenching with 1 mL of H₂O and 5mL of 1 N NaOH. The mixture was extracted with CH₂Cl₂ (30 mL×2). Thecombined extracts were dried (K₂CO₃), concentrated, and purified byflash chromatography on silica gel (chloroform: MeOH:2.0 M NH₃ inMeOH=100:5:1) to afford the product (0.479 g, 77%) as an colorless oil.

c. (S)-Amino-3-[4-(2-pyridyl)piperidin-1-yl]propane

A solution of(S)-N-(tert-butoxycarbonyl)amino-3-[4-(2-pyridyl)piperidin-1-yl]propane(0.460 g, 1.44 mmol) in CH₂Cl₂ (10 mL) and TFA (5 mL) was stirred for 12hours at room temperature. The mixture was concentrated at reducedpressure and the residue was washed with 20% NaOH, and extracted withextracted with CH₂Cl₂ (50 mL×2). The combined extracts were dried(K₂CO₃), concentrated to yield the product (0.209 g, 66%) withoutfurther purification.

d. 3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxylicacid-{2-[4-(2-pyridyl) piperidin-1-yl]-1- methyl-ethyl}-amidehydrochloride (Compound 19)

4-(2-Pyridinyl)piperidinyl-N-(1-methyl)ethylamine (25 mg, 0.114 mmol)was added to a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as eluent to give 10 mg product (55%). MH⁺=487. The HCl salt wasprepared by treatment with 1 N HCl in ether.

10. Substituted Morpholinone Example:N-4-(2-[1-(2,4-Difluorobenzoyl)-4-piperidyl]aminoethyl)-3-(3,4-difluorophenyl)-2,2-dimethyl-5-oxo-4-morpholinecarboxamideHydrochloride (Compound 20) (Scheme 5)

a. 4-(2,4-Difluorobenzoyl)piperidinone

To a suspension of 4-piperidinone monohydrate hydrochloride (2.00 g,13.28 mmol) in CH₂Cl₂ (40 mL) and triethylamine (5.0 mL) was added2,4-difluorobenzoyl chloride (2.84 g, 15.93 mmol). The resulting mixturewas stirred at room temperature for 5 hours before quenching withaqueous NaHCO₃ (30 mL). Extracted with EtOAc (3×50 mL), dried (MgSO₄),and concentrated to a residue which was purified by flash chromatography(EtOAc:Hexanes 9:1 to 1:1 ) afford product as an oil (2.25 g, 71%).

b. 2-{[4-(2,4-Difluorobenzoyl)piperidinyl]amino}ethylamine

A solution of 4-(2,4-difluorobenzoyl)piperidinone (1.50 g, 6.27 mmol) inbenzene (40 mL) and ethylenediamine (4.0 mL) was refluxed for 6 hours.The resulting mixture was concentrated to a residue which was dissolvedin MeOH (30 mL). The mixture was cooled (0° C.) and NaBH₄ (1.0 g, 26.4mmol) was slowly added. After stirred for an hour, the mixture wasconcentrated and quenched with 1 N NaOH (50 mL). The mixture wasextracted with CH₂Cl₂ (5×20 mL), dried (K₂CO₃), and was concentrated.The residue was purified by flash chromatography (CHCl₃-MeOH-2 M NH₃ inMeOH 100:10:2 to 100:20:5) to afford the product as an pale yellow solid(670 mg, 38%).

c. 3-(3,4-Difluorophenyl)-2,2-dimethyl-5-oxo-morpholine-4-carboxylicacid-{2-[1-(2,4-difluoro benzoylpiperidin-4-yl]-aminoethylamidehydrochloride

4-N-(2,4-Difluorobenzoyl)-piperidinyl-amino-ethylamine (25 mg, 0.088mmol) was added to a stirred solution of (±)-4-nitrophenyl2,2-dimethyl-3-(3,4-difluorophenyl)-5-oxo-morpholinecarboxylate (15 mg,0.037 mmol) in CH₂Cl₂ (5 mL). The resulting mixture was stirred at roomtemperature overnight and purified by prep. TLC on silica gel usingEtOAc as eluent to give 10 mg product (49%). MH⁺=551. The HCl salt wasprepared by treatment with 1 N HCl in ether.

IV. Synthesis of Morpholine Example (Scheme 6) 1. Synthesis of3-(3,4-difluoro-phenyl)-morpholine-4-carboxylicAcid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide (Compound 21)

a. 3-(3,4-Difluoro-phenyl)-morpholine

To a suspension of LiAlH₄ (6.0 mmol, 0.23 g) in 25.0 mL of Et₂O wasadded a solution of 5-(3,4-difluoro-phenyl)-morpholin-3-one (2.0 mmol,0.42 g) in 20.0 mL Et₂O and 5.0 mL THF at room temperature. Theresulting suspension was heated to reflux for 2 hours and was thenquenched with water and aq. NaOH solution. The solid was filtered offand the filtrate was dried over Na₂SO₄. The filtrate was then decantedand the solvent was removed in vacuo to obtain5-(3,4-difluoro-phenyl)morpholine as a viscous oil. It was converted toits hydrochloride salt for its analysis. Yellow powder. M.P.=171-173°C.; Mass spec. 200 (M+1, 100%). Analysis calculated for C₁₀H₁₂NOF₂Cl.0.5acetone: C, 51.96; H, 5.61; N, 5.41. Found: C, 51.98; H, 5.70; N, 5.34.

b. 3-(4,4-Diphenyl-piperidin-1-yl)-propyl]-carbamic acid-4-nitro-phenylester

To a solution containing 3-(4,4-diphenyl-piperidin-1-yl)-propylamine(0.8 mmol, 0.24 g) and triethylamine (0.96 mmol, 0.13 mL) in 10 mL ofTHF was added 4-nitrophenylchloroformate (0.94 mmol, 0.19 g) at 0° C.The solution was allowed to reach room temperature over 1 hour. Thesolvent was removed and the product was passed through a short silicagel column with EtOAc as an eluent (Rf=0.25).3-(4,4-Diphenyl-piperidin-1-yl)propyl]-carbamic acid-4-nitro-phenylester was obtained as a yellow oil which was immediately used in thenext step.

c. 3-(3,4-Difluoro-phenyl)-morpholine-4-carboxylicacid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide

To a solution of 3-(4,4-diphenyl-piperidin-1-yl)propyl]-carbamicacid-4-nitro-phenyl ester (0.35 mmol, 150 mg) in 10.0 mL THF was added3-(3,4-difluorophenyl)-morpholine (0.4 mmol, 50 mg) at room temperature.The solvent was removed in vacuo and the residue was subjected to silicagel column chromatography (8:1 EtOAc/MeOH as the eluting system).3-(3,4-Difluoro-phenyl)-morpholine-4-carboxylicacid[3-(4,4-diphenyl-piperidin-1-yl)-propyl]-amide was obtained as apale yellow oil which was converted into its hydrochloride salt bytreatment with 1 N HCl in ether (34 mg, 61%). Yellow sticky solid.M.P.=71-74° C.; Mass spec. 520 (M+1, 100%); Analysis calculated forC₃₁H₃₆N₃O₂F₂Cl.0.8 CH₂Cl₂: C, 61.21; H, 6.07; N, 6.73. Found: C, 61.45;H, 6.35; N, 6.27.

V. General Syntheses of Morpholinones and Morpholines

The examples described in Sections I-IV are merely illustrative of themethods used to synthesize morpholine and morpholinone derivatives.Further derivatives may be obtained utilizing the methods shown inSchemes 7-22. The substituents in Schemes 7-22 are described in theDetailed Description.

It may be necessary to incorporate protection and deprotectionstrategies for substituents such as amino, amido, carboxylic acid, andhydroxyl groups in the synthetic methods described above to formmorpholine and morpholinone derivatives. Methods forprotection/deprotection of such groups are well-known in the art, andmay be found, for example in Greene, T. W. and Wuts, P. G. M. (1991)Protective Groups in Organic Synthesis. 2nd Edition John Wiley & Sons,New York.

VI. Oral Composition

As a specific embodiment of an oral composition of a compound of thisinvention, 100 mg of one of the compounds described herein is formulatedwith sufficient finely divided lactose to provide a total amount of 580to 590 mg to fill a size O hard gel capsule.

VII. Pharmacological Profiles of the Compounds in Cloned HumanAdrenergic Receptors

Binding affinities were measured for selected compounds of the inventionat six cloned human α₁ and α₂ receptor subtypes, as well as at theL-type calcium channel. The protocols for these experiments are givenbelow.

1. Protocol for the Determination of the Potency of α₁ Antagonists

The activity of compounds at the different human receptors wasdetermined in vitro using cultured cell lines that selectively expressthe receptor of interest. These cell lines were prepared by transfectingthe cloned cDNA or cloned genomic DNA or constructs containing bothgenomic DNA and cDNA encoding the human a-adrenergic receptors asfollows:

α_(1d) Human Adrenergic Receptor:

The entire coding region of α_(1d) (1719 bp), including 150 base pairsof 5′ untranslated sequence (5′ UT) and 300 bp of 3′ untranslatedsequence (3′ UT), was cloned into the BamHI and ClaI sites of thepolylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.HR.The construct involved the ligation of partial overlapping humanlymphocyte genomic and hippocampal cDNA clones: 5′ sequence werecontained on a 1.2 kb SmaI-XhoI genomic fragment (the vector-derivedBamHI site was used for subcloning instead of the internalinsert-derived SmaI site) and 3′ sequences were contained on an 1.3 kbXhoI-ClaI cDNA fragment (the ClaI site was from the vector polylinker).Stable cell lines were obtained by cotransfection with the plasmidα1A/EXJ (expression vector containing the α_(1a) receptor gene (oldnomenclature)) and the plasmid pGCcos3neo (plasmid containing theaminoglycoside transferase gene) into LM(tk−) cells using calciumphosphate technique. The cells were grown, in a controlled environment(37° C., 5% CO₂), as monolayers in Dulbecco's modified Eagle's Medium(GIBCO, Grand Island, N.Y.) containing 25 mM glucose and supplementedwith 10% bovine calf serum, 100 units/ml penicillin g, and 100 μg/mlstreptomycin sulfate. Stable clones were then selected for resistance tothe antibiotic G-418 (1 mg/ml), and membranes were harvested and assayedfor their ability to bind [³H]prazosin as described below (see“Radioligand Binding assays”).

The cell line expressing the human α_(1d) receptor used herein wasdesignated L-α_(1A) (old nomenclature) and was deposited with theAmerican Type Culture Collection, 12301 Parklawn Drive, Rockville, Md.20852, U.S.A. under the provisions of the Budapest Treaty for theInternational Recognition of the Deposit of Microorganisms for thePurposes of Patent Procedure. The cell line expressing the human α_(1d)receptor, was accorded ATCC Accession No. CRL 11138, and was depositedon Sep. 25, 1992.

α_(1b) Human Adrenergic Receptor:

The entire coding region of α_(1b) (1563 bp), including 200 base pairsand 5′ untranslated sequence (5′ UT) and 600 bp of 3′ untranslatedsequence (3′ UT), was cloned into the EcoRI site of pCEXV-3 eukaryoticexpression vector. The construct involved ligating the full-lengthcontaining EcoRI brainstem cDNA fragment from λ ZapII into theexpression vector. Stable cell lines were selected as described above.The cell line used herein was designated L-α_(1B) and was deposited withthe American Type Culture Collection, 12301 Parklawn Drive, Rockville,Md. 20852, U.S.A. under the provisions of the Budapest Treaty for theInternational Recognition of the Deposit of Microorganisms for thePurposes of Patent Procedure. The cell line L-α_(1B) was accorded ATCCAccession No. CR 11139, on Sep. 29, 1992.

α_(1a) Human Adrenergic Receptor:

The entire coding region of α_(1a) (1401 bp), including 400 base pairsof 5′ untranslated sequence (5′ UT) and 200 bp of 3′ untranslatedsequence (3′ UT), was cloned into the KpnI site of thepolylinker-modified pCEXV-3-derived eukaryotic expression vector,EXJ.RH. The construct involved ligating three partial overlappingfragments: a 5′ 0.6 kb HincII genomic clone, a central 1.8 EcoRIhippocampal cDNA clone, and a 3′ 0.6Kb PstI genomic clone. Thehippocampal cDNA fragment overlaps with the 5′ and 3′ genomic clones sothat the HincII and PstI sites at the 5′ and 3′ ends of the cDNA clone,respectively, were utilized for ligation. This full-length clone wascloned into the KpnI site of the expression vector, using the 5′ and 3′KpnI sites of the fragment, derived from vector (i.e., pBluescript) and3′-untranslated sequences, respectively. Stable cell lines were selectedas described above. The stable cell line expressing the human α_(1a)receptor used herein was designated L-α_(1c) (old nomenclature) and wasdeposited with the American Type Culture Collection, 12301 ParklawnDrive, Rockville, Md. 20852, U.S.A. under the provisions of the BudapestTreaty for the International Recognition of the Deposit ofMicroorganisms for the Purposes of Patent Procedure. The cell lineexpressing the human α_(1a) receptor was accorded Accession No. CR11140, on Sep. 25, 1992.

Radioligand Binding Assays for α₁ receptors:

Transfected cells from culture flasks were scraped into 5 ml of 5 mMTris-HCl, 5 mM EDTA, pH 7.5, and lysed by sonication. The cell lysateswere centrifuged at 1000 rpm for 5 min at 4° C., and the supernatant wascentrifuged at 30,000×g for 20 min at 4° C. The pellet was suspended in50 mM Tris-HCl, 1 mM MgCl₂, and 0.1% ascorbic acid at pH 7.5. Binding ofthe α₁ antagonist [³H]prazosin (0.5 nM, specific activity 76.2 Ci/mmol)to membrane preparations of LM(tk−) cells was done in a final volume of0.25 ml and incubated at 37° C. for 20 min. Nonspecific binding wasdetermined in the presence of 10 μg phentolamine. The reaction wasstopped by filtration through GF/B filters using a cell harvester.Inhibition experiments, routinely consisting of 7 concentrations of thetested compounds, were analyzed using a non-linear regressioncurve-fitting computer program to obtain Ki values.

α₂ Human Adrenergic Receptors:

To determine the potency of α₁ antagonists at the α₂ receptors, LM(tk−)cell lines stably transfected with the genes encoding the α_(2a),α_(2b), and α_(2c) receptors were used. The cell line expressing theα_(2a) receptor is designated L-α_(2A), and was deposited on Nov. 6,1992 under ATCC Accession No. CRL 11180. The cell line expressing theα_(2b) receptor is designated L-NGC-α_(2B), and was deposited on Oct.25, 1989 under ATCC Accession No. CRL10275. The cell line expressing theα_(2c) receptor is designated L-α_(2C), and was deposited on Nov. 6,1992 under ATCC Accession No. CRL-11181. All the cell lines weredeposited with the American Type Culture Collection, 12301 ParklawnDrive, Rockville, Md. 20852, U.S.A. under the provisions of the BudapestTreaty for the International Recognition of the Deposit ofMicroorganisms for the Purposes of Patent Procedure. Cell lysates wereprepared as described above (see Radioligand Binding Assays), andsuspended in 25 mM glycylglycine buffer (pH 7.6 at room temperature).Equilibrium competition binding assay were performed using[3H]rauwolscine (0.5 nM), and nonspecific binding was determined byincubation with 10 μM phentolamine. The bound radioligand was separatedby filtration through GF/B filters using a cell harvester.

Determination of the Activity of α₁ Antagonists at Calcium Channels:

The potency of α₁ antagonists at calcium channels may be determined incompetition binding assays of [3H]nitrendipine to membrane fragments ofrat cardiac muscle, essentially as described by Glossman and Ferry(Methods in Enzymology 109:513-550, 1985). Briefly, the tissue is mincedand homogenized in 50 mM Tris-HCl (pH 7.4) containing 0.1 mMphenylmethylsulfonyl fluoride. The homogenates are centrifuged at 1000 gfor 15 minutes, and the resulting supernatant centrifuged at 45,000 gfor 15 minutes. The 45,000 g pellet is suspended in buffer andcentrifuged a second time. Aliquots of membrane protein are thenincubated for 30 minutes at 37° C. in the presence of [3H]nitrendipine(1 nM), and nonspecific binding determined in the presence of 10 μgnifedipine. The bound radioligand is separated by filtration throughGF/B filters using a cell harvester.

The compounds described above were assayed using cloned human alphaadrenergic receptors. The preferred compounds were found to be selectiveα_(1a) antagonists. The binding affinities of several compounds areillustrated in the following table.

Binding affinities of selected compounds of the present invention atcloned human α_(1d), α_(1b) and α_(1a) receptors. (h=human)

hα_(1d) hα_(1b) hα_(1a) Compound K_(i) (nM) K_(i) (nM) K_(i) (nM) 1306.7 243.6 1.6 4 3162.3 3630.8 32.0 7 204.2 245.5 12.6 14 4200.8 1456.62.6 17 579.9 464.2 3.8

What is claimed is:
 1. A compound having the structure:

wherein W is O; where Y is independently O or S; where R₂ is aryl;wherein the aryl may be substituted with one or more of F; Cl; Br; I;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; and wherein n independently isan integer from 0 to 7 inclusive; wherein R₈ is independently H,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or cycloalkenyl; where R₃ isindependently H; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; where R₄ is H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl orbenzyl; wherein the phenyl or benzyl may be substituted with one or moreof F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,or carboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl oralkynyl; or C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; and wherein tindependently is an integer from 1 to 4 inclusive; where R₅ is H,—(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl; wherein the phenylor benzyl may be substituted with one or more of F; Cl; Br; I; —CN;—NO₂; —N(R₆)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; where R₆ is H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl orbenzyl; wherein the phenyl or benzyl may be substituted with one or moreof F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₂-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl,or carboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; where R₇ is H,—(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl, C₅-C₇ cycloalkenyl, or phenyl or benzyl; wherein the phenylor benzyl may be substituted with one or more of F; Cl; Br; I; —CN;—NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; where each R₈, n, and tindependently is as defined above; where R₁ is

wherein each R₉ is H; straight chained or branched C₁-C₇ alkyl,hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, orpolyfluoroalkyl; straight chained or branched C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C₅-C₇cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl maybe substituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl; wherein each R₁₀ is H; F;—OH; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈; —CN; —NO₂; —N(R₈)₂; aryl or heteroaryl; straightchained or branched C₁-C₇ alkyl, hydroxyalkyl, aminoalkyl,carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;straight chained or branched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl,monofluorocycloalkyl or polyfluorocycloalkyl; or C₅-C₇ cycloalkenyl;wherein the alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may besubstituted with one or more aryl or heteroaryl; wherein the aryl orheteroaryl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)COR₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl, monofluorocycloalkyl, orpolyfluorocycloalkyl; or C₅-C₇ cycloalkenyl; wherein each R₁₁ isindependently H, —(CH₂)_(t)YR₈, —(CH)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈,—(CH₂)_(t)CO₂R₈, —(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂,—CO₂R₈, straight chained or branched C₁-C₇ alkyl, straight chained orbranched C₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇cycloalkenyl; wherein each R₁₂ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, straight chained or branched C₁-C₇alkyl, straight chained or branched C₂-C₇ alkenyl or alkynyl, C₃-C₇cycloalkyl, or C₅-C₇ cycloalkenyl; wherein R₁₃ is H, C₁-C₇ alkyl,—C(O)R₂, aryl, heteroaryl, C₁-C₇ alkyl substituted with one or two aryl,or C₁-C₇ alkyl substituted with one or two heteroaryl; wherein the arylor heteroaryl may be substituted with one or more of F; Cl; Br; I; —CN;—NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chained or branchedC₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl;straight chained or branched C₂-C₇ aminoalkyl, alkenyl or alkynyl; C₃-C₇cycloalkyl; or C₅-C₇ cycloalkenyl; wherein R₁₄ is H, straight chained orbranched C₁-C₇ alkyl; wherein each m is independently 1 or 2; whereineach p is independently an integer from 0 to 2 inclusive; wherein J is

wherein each R₁₅ is independently H, —(CH₂)_(t)YR₈,—(CH₂)_(t)C(Y)N(R₈)₂, —(CH₂)_(t)C(Y)R₈, —(CH₂)_(t)CO₂R₈,—(CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN, —C(Y)R₈, —C(Y)N(R₈)₂, —CO₂R₈, straightchained or branched C₁-C₇ alkyl, straight chained or branched C₂-C₇alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl; whereineach R₁₆ is independently H, —(CH₂)_(t)YR₈, —(CH₂)_(t)C(Y)N(R₈)₂,—(CH₂)_(t)C(Y) R₈, —(CH₂)_(t)CO₂R₈, —CH₂)_(t)N(R₈)₂, —(CH₂)_(t)CN,straight chained or branched C₁-C₇ alkyl, straight chained or branchedC₂-C₇ alkenyl or alkynyl, C₃-C₇ cycloalkyl, or C₅-C₇ cycloalkenyl;wherein each R₁₇ is independently H; F; —(CH₂)_(t)YR₈;—(CH₂)_(t)C(Y)N(R₈)₂; —(CH₂)_(t)C(Y)R₈; —(CH₂)_(t)CO₂R₈;—(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN; —C(Y)R₈; —C(Y)N(R₈)₂; —CO₂R₈; straightchained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl,aminoalkyl, or carboxamidoalkyl; straight chained or branched C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl; whereineach R₁₈ is independently H; F; —(CH₂)_(t)YR₈; —(CH₂)_(t)C(Y)N(R₈)₂;—(CH₂)_(t)C(Y) R₈; —(CH₂)_(t)CO₂R₈; —(CH₂)_(t)N(R₈)₂; —(CH₂)_(t)CN;straight chained or branched C₁-C₇ alkyl, monofluoroalkyl,polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained orbranched C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇cycloalkenyl; wherein L is S, O, or N(R₈); or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein thecompound comprises the (+) enantiomer.
 3. The compound of claim 1,wherein the compound comprises the (−) enantiomer.
 4. The compound ofclaim 1, wherein R₉ is aryl or heteroaryl, wherein the aryl orheteroaryl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; and wherein R₁₀ is H; —CN; —OH;—CO₂R₈; aryl or heteroaryl; wherein the aryl or heteroaryl may besubstituted with one or more of F; Cl; Br; I; —(CH₂)_(n)YR₈;—(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; —CN; —NO₂;—N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl.
 5. The compound of claim 4 havingthe structure:

wherein R₂ is phenyl; wherein the phenyl may be substituted with one ormore of F; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈ ; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈; straight chainedor branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl.
 6. Thecompound of claim 5 wherein J is


7. The compound of claim 6 wherein R₁ is


8. The compound of claim 7, wherein R₉ is phenyl or pyridyl, wherein thephenyl or pyridyl may be substituted with one or more of F; Cl; Br; I;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y) R₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)CO₂R₈;—CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained or branched C₁-C₇ alkyl,monofluoroalkyl, or polyfluoroalkyl; wherein R₁₀ is H, —CN, —OH, —CO₂R₈,or phenyl; wherein the phenyl may be substituted with one or more of F;Cl; Br; I; —(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)R₈; —(CH₂)_(n)C(Y)N(R₈)₂;—(CH₂)_(n)CO₂R₈, —CN; —NO₂; —N(R₈)₂; —SO₂R₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl; and whereinR₁₃ is phenyl; wherein the phenyl may be substituted with one or more ofF; Cl; Br; I; —CN; —NO₂; —N(R₈)₂; —SO₂R₈; —(CH₂)_(n)C(Y)R₈;—(CH₂)_(n)YR₈; —(CH₂)_(n)C(Y)N(R₈)₂; —(CH₂)_(n)COR₈; straight chained orbranched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, orcarboxamidoalkyl; straight chained or branched C₂-C₇ aminoalkyl,alkenyl, or alkynyl; C₃-C₇ cycloalkyl; or C₅-C₇ cycloalkenyl.
 9. Apharmaceutical composition comprising a therapeutically effective amountof the compound of claim 1 and a pharmaceutically acceptable carrier.10. The pharmaceutical composition of claim 9, wherein the amount of thecompound is an amount from about 0.01 mg to about 800 mg.
 11. Thepharmaceutical composition of claim 10, wherein the amount of thecompound is from about 0.01 mg to about 500 mg.
 12. The pharmaceuticalcomposition of claim 11, wherein the amount of the compound is fromabout 0.01 mg to about 250 mg.
 13. The pharmaceutical composition ofclaim 12, wherein the amount of the compound is from about 0.1 mg toabout 60 mg.
 14. The pharmaceutical composition of claim 13, wherein theamount of the compound is from about 1 mg to about 20 mg.
 15. Thepharmaceutical composition of claim 9, wherein the carrier is a liquidand the composition is a solution.
 16. The pharmaceutical composition ofclaim 9, wherein the carrier is a solid and the composition is a tablet.17. The pharmaceutical composition of claim 9, wherein the carrier is agel and the composition is a suppository.
 18. The pharmaceuticalcomposition of claim 9, wherein the compound additionally does not causea fall in blood pressure at dosages effective to alleviate benignprostatic hyperplasia.
 19. A method of treating a subject suffering frombenign prostatic hyperplasia which comprises administering to thesubject an amount of the compound of claim 1 effective to treat benignprostatic hyperplasia.
 20. A method of claim 19, wherein the compoundadditionally does not cause a fall in blood pressure at dosageseffective to alleviate benign prostatic hyperplasia.
 21. The method ofclaim 20, wherein the compound effects treatment of benign prostatichyperplasia by relaxing lower urinary tract tissue.
 22. The method ofclaim 21, wherein lower urinary tract tissue is prostatic smooth muscle.23. A method of treating a subject suffering from high intraocularpressure which comprises administering to the subject an amount of thecompound of claim 1 effective to lower intraocular pressure.
 24. Amethod of treating a subject suffering from a disorder associated withhigh cholesterol which comprises administering to the subject an amountof the compound of claim 1 effective to inhibit cholesterol synthesis.25. A method of treating a subject suffering from cardiac arrhythmiawhich comprises administering to the subject an amount of the compoundof claim 1 effective to treat cardiac arrhythmia.
 26. A method oftreating a subject suffering from impotency which comprisesadministering to the subject an amount of the compound of claim 1effective to treat impotency.
 27. A method of treating a subjectsuffering from sympathetically mediated pain which comprisesadministering to the subject an amount of the compound of claim 1effective to treat sympathetically mediated pain.
 28. A method oftreating a subject suffering from migraine which comprises administeringto the subject an amount of the compound of claim 1 effective to treatmigraine.
 29. A method of treating a disease which is susceptible totreatment by antagonism of the α_(1a) receptor which comprisesadministering to the subject an amount of the compound of claim 1effective to treat the disease.
 30. A method of treating a subjectsuffering from benign prostatic hyperplasia which comprisesadministering to the subject an amount of the compound of claim 1 incombination with a 5-alpha reductase inhibitor effective to treat benignprostatic hyperplasia.
 31. The method of claim 30, wherein the 5-alphareductase inhibitor is finasteride.
 32. A pharmaceutical compositioncomprising a therapeutically effective amount of the compound of claim 1in combination with a therapeutically effective amount of finasterideand a pharmaceutically acceptable carrier.
 33. The pharmaceuticalcomposition of claim 32, wherein the compound is present in an amountfrom about 0.01 mg to about 800 mg and the therapeutically effectiveamount of the finasteride is about 5 mg.
 34. The pharmaceuticalcomposition of claim 33, wherein the compound is present in an amountfrom about 0.1 mg to about 60 mg and the therapeutically effectiveamount of finasteride is about 5 mg.
 35. The pharmaceutical compositionof claim 34, wherein the compound is present in an amount from about 1mg to about 20 mg and the therapeutically effective amount offinasteride is about 5 mg.
 36. A method of relaxing lower urinary tracttissue which comprises contacting the lower urinary tract tissue with anamount of the compound of claim 1 effective to relax lower urinary tracttissue.
 37. The method of claim 36, wherein the lower urinary tracttissue is prostatic smooth muscle.
 38. A method of relaxing lowerurinary tract tissue in a subject which comprises administering to thesubject an amount of the compound of claim 1 effective to relax lowerurinary tract tissue.
 39. The method of claim 38, wherein the lowerurinary tract tissue is prostatic smooth muscle.
 40. A pharmaceuticalcomposition made by combining a therapeutically effective amount of thecompound of claim 1 and a pharmaceutically acceptable carrier.
 41. Apharmaceutical composition made by combining a therapeutically effectiveamount of the compound of claim 1 with a therapeutically effectiveamount of finasteride and a pharmaceutically acceptable carrier.
 42. Aprocess for making a pharmaceutical composition comprising combining atherapeutically effective amount of the compound of claim 1 and apharmaceutically acceptable carrier.
 43. A process for making apharmaceutical composition comprising combining a therapeuticallyeffective amount of the compound of claim 1 with a therapeuticallyeffective amount of finasteride and a pharmaceutically acceptablecarrier.